TW384291B - Compounds for reinforcing the contraction of cardiac muscles and reducing the rate of heart beats - Google Patents

Abstract

Disclosed are cardiotonic medicines containing, as the active ingredient, at least one of compounds of formula (I) and their pharmacologically acceptable salts when they form salts, wherein X1 and X2 do not exist or represents an oxygen atom; A represents OH or a C1-C4 alkyl group, etc.; R3 and R4 each represents a hydrogen atom, a C1-C4 acyloxy group; B represents a hydrogen atom or may form a chemical bond along with A; X is an oxygen atom , nitrogen, sulfur, etc.; R1 and R2 each represents a hydrogen atom, a C1-C4 alkyl group, etc., or they may together form a 1,4-butylene or 1,5-pentylene group. The compounds having a strong activity of reinforcing the contraction of cardiac muscles and a strong activity of reducing the rate of heart beats. As they are not toxic, they are useful as cardiotonic medicines.

Description

Printed by A7 B7 of the Consumer Cooperatives of the Central Bureau of Quasi-Staff of the Ministry of Economic Affairs 5. Description of the Invention (1) The present invention relates to pharmacologically active benzopiperan derivatives as a package. Cardiac dysfunction in mammals including humans Uses for treatment. Japanese Unexamined Patent Publication No. 2-4 7 9, Japanese Unexamined Patent Publication No. 2 — 4 9 7 8 8, Japanese Unexamined Patent Publication No. 2 — 1 5 2 9 7 4 Japanese Unexamined Patent Publication No. 5 — 4 3 4 3 Patent 4 9 0 0 7 5 2, European Patent 3 2 7 1 2 7, European Patent 4 9 2 3 9 1 have disclosed that benzopiperan derivatives can be used as a treatment for hypertension , Circulatory disorders such as atherosclerosis, arrhythmia, etc., and as a hair growth promoter to treat hair loss, etc., but there is no mention of treatment of cardiac dysfunction. The inventors have conducted in-depth studies on compounds that have low activation of potassium channels and have no heart-inhibiting effect, but can enhance cardiac contractility among benzopiperan derivatives. As a result, they have found that the compounds represented by formula (I) have extremely The strong heart and heart effect complete the present invention. The compound used in the present invention is a compound represented by formula (I) and its optical isomers and stereoisomers, and when it is a compound capable of forming amidine, it is a pharmaceutically acceptable amidine.

[In the formula, X1 and X2 are not present or represent an oxygen atom; X is an oxygen atom, a sulfur atom, a nitrogen atom, (the nitrogen atom can be applied to the Chinese National Standard (CNS) A4 specification (210X297 mm) by this paper size) 83. 3. 10,000 (Please read the notes on the back before filling this page)

A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (2) Hydrogen atom or Cl ~ C4 alkyl substituted), c (〇), c (S) or C (N-CN); A series Represents a hydrogen atom, a hydroxyl group, or oc (〇) R5 (RS represents Ci ~ C4 alkyl), or a single bond with B: B represents a hydrogen atom, or a single bond with A;. R1 and R2 may be the same as or different from each other and represent a hydrogen atom or a C 1 ~ C4 alkyl group, or R1 and R2 together represent a 1, 4-butylene group or a 1,5-butylene group which may be substituted by a C i ~ C4 alkyl group R 3 and R 4 may be the same or different from each other, and represent a hydrogen atom, a straight or branched chain alkyl group of Ci ~ C6 {the academy system may be arbitrarily substituted by a halogen atom, a benzyl group, a c2 ~ c5 alkyloxycarbonyl group, Hydroxyl, C: L ~ c4 · alkoxy, CH (OR> 2 (R represents Ci—C4 alkyl), phenyl (can be optionally substituted with halogen atom, hydroxyl, Ci ~ c4 alkoxy), Formamyl, gas or nitro substituted}, Cl ~ c6 linear or branched alkenyl {The alkene group (can be optionally _ prime atom, carboxyl, C 2 ~ C 5 alkoxycarbonyl, hydroxyl, CxaCd alkoxy, CH (OR) 2 (R series table (Ci-Ca alkyl), phenyl (can be arbitrarily substituted with a halogen atom, a hydroxyl group, Cl ~ C 4 alkoxy group}, formyl, cyano or nitro group}, C 2 ~ C 6 Chain or branched chain alkynyl {The alkynyl system can be arbitrarily substituted by a halogen atom, a carboxyl group, a c2 ~ c5 alkoxycarbonyl group, a hydroxyl group, a Ci ~ C4 alkoxy group, and a CH (〇R) 2 (R system means Ci—C4 alkane ≫, phenyl (optionally substituted with a halogen atom, a hydroxyl group, Ci ~ C 4 alkoxy group}, methyl formyl, cyano or nitro group}, (: 3 ~ (: 6cycloalkyl { The cycloalkyl group can be arbitrarily selected by a halogen atom, a carboxyl group, (: 2 ~ (: 5alkoxycarbonyl group, hydroxyl group) The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 83.3.10,000 -5-(Please Read the notes on the back before filling this page) * Packing. Order A7 B7 V. Description of the invention (3), Ca ~ (: 4 alkoxy, CH (OR) 2 (R means Ci—Cd alkyl), Phenyl (can be arbitrarily substituted with a halogen atom, a hydroxyl group, Ci ~ C4 alkoxy group}, formyl, cyano, or nitro}}, phenyl (can be arbitrarily substituted with a halogen atom, a hydroxyl group, a C2-C4 alkyl group Oxygen arbitrary Substitution), or C (= Y) ZRe (Y represents oxygen, sulfur or nr7 (R7 represents hydrogen, cyano, nitro, Ci ~ C4 alkyl, Ci ~ C 4 alkoxy or C ◦ 2 R 8 (R 8 represents c C 4 alkyl)), Z represents oxygen, sulfur or NR9 (R 9 represents hydrogen, Ci ~ C 6 straight or branched alkyl {The alkyl system Can be arbitrarily selected by halogen atom, carboxyl, C2 ~ C5 alkoxycarbonyl, hydroxyl, C1 ~ C4 alkoxy, CH (OR) 2 (R means Ci—C4 alkyl), phenyl (can be arbitrarily selected by halogen atom, Hydroxyl, CiwC 4 alkoxy optionally substituted), methyl, cyano or nitro substituted}, linear or branched alkenyl groups of c1 to c6 {the alkenyl group can be arbitrarily substituted by a halogen atom, a carboxyl group, c2 ~ C5 alkoxycarbonyl, hydroxy, Ci-Cd alkoxy, CH (OR) 2 (R means Cl—C4 alkyl), phenyl (can be arbitrarily selected by halogen atom, hydroxy, Central Bureau of Standards, Ministry of Economic Affairs, Consumer Consumption Cooperative Printed 4 alkoxy groups are optionally substituted), methylamino, fluoro or nitro substituted}, C2 ~ C6 straight or branched chain alkynyl {The alkynyl system can be optionally substituted by a halogen atom, a carboxyl group, c2 ~ c5 alkoxycarbonyl , Hydroxy, Ci-Cd alkoxy, CH (OR) 2 (R means Ci—C4 alkyl), phenyl (can be optionally substituted by halogen atom, hydroxyl, ◦: ~ (: < alkoxy ), Methylamino, cyano or nitro substituted}, C3 ~ C 6 cycloalkyl {The cycloalkyl system can be optionally substituted with a halogen atom, a carboxyl group, a 02 ~ 05 alkoxycarbonyl group, a hydroxyl group, Ci ~ C4 Hospital Oxygen 'CH (OR) 2 (R means Ci—. 83. 3.10,000 (Please read the precautions on the back before filling out this page) This paper size applies to China National Standard (' CNS) A4 specification (210X297) (Centi) 6-five. Description of the invention (4) C4 alkyl), phenyl (optionally substituted with halogen atom, hydroxyl, alkoxy), methyl substituted, cyano or nitro}, phenyl ( It can be arbitrarily substituted with halogen atom, hydroxyl group, CL-C4 alkoxy group), R6 series hydrogen atom, Ci-Ce linear or branched alkyl group {the alkyl group can be arbitrarily substituted with halogen atom, carboxyl group, C2 ~ (: 5 alkoxycarbonyl, hydroxyl, C! ~ C4 alkoxy, CH (OR) 2 (R means Ci—C4 alkyl), phenyl (can be arbitrarily halogen atom, hydroxyl, Ci-C # alkoxy base Intentionally substituted), methylformyl, cyano or nitro substituted}, C2 ~ C6 linear or branched alkenyl {The alkenyl group can be optionally substituted by a halogen atom, a carboxyl group, a C2 ~ C5 oxocarbonyl group, Hydroxyl, Ci-Cd alkoxy, CH (OR) 2 (R represents Ci-Ci alkyl), phenyl (can be optionally substituted by halogen atom, hydroxyl, (:, ~ (: 4 alkoxy. Any substitution ), Methylamino, cyano or nitro substituted}, C2 ~ C6 linear or branched block {The alkynyl group can be optionally substituted by a halogen atom, a carboxyl group, a C 2 ~ C 5 alkoxycarbonyl group, a hydroxyl group, (: 1 ~ (: 4 alkoxy, CH (OR) 2 (R represents Cx-C4 alkyl), phenyl (can be arbitrarily substituted with a halogen atom, hydroxyl "Ci-Cd alkoxy), Formyl, cyano or nitro substitution}, c3 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) ~ C6 cycloalkyl {The cycloalkyl is optional A halogen atom, a carboxyl group, a C2 ~ C5 alkoxycarbonyl group, a hydroxyl group, a CiaCa alkoxy group, CH (OR) 2 (R stands for Ci—C4 alkyl group), a phenyl group (can be arbitrarily replaced by a halogen atom, hydroxyl group, Ci-Ca Alkoxy Intentionally substituted) Formamyl, cyano or nitro substituted}, phenyl (optionally substituted with halogen atom, fluorenyl, C: -C4 alkoxy) or R 3 and R 4 together represent, 4 butyl or 1,5-pentyl {The butyl or pentyl can be divided into paper sizes applicable to the Chinese National Standard (CNS) A4 specification (21CIX297 mm) ~~~~

Do not arbitrarily be Ca-C: 4 alkyl, taroyl (can be arbitrarily substituted with halogen atom, hydroxyl group, CiaC * oxygen group), halogen atom, V. Description of the invention (?) (Please read the notes on the back first Fill out this page again) 0R10 (R1. Represents a hydrogen atom, .Ci ~ c 4 alkyl, CORiMR11 represents Ci ~ c4 alkyl), nitro, s03H or P03Ρ2) arbitrary substitution}, or ruler 3 and 1 ^ 4 — starting from i, 4-butyl or 1 '5-pentyl {The butyl or pentoyl can be arbitrarily selected by C i ~ C 4 alkyl, phenyl (can be arbitrarily Prime atom, hydroxy 'CC 4 oxo optionally substituted), halogen atom, OR 10 (R 10 is a hydrogen atom, (^ ~ (^ alkyl, C0R11 (R11 is a c C 4 oxo)), nitro , S Ο 3Η or Ρ Ο 3Η 2) arbitrarily substituted}, or R 3 and R 4 together represent (c Η 2) mX 4 (C Η 2)! (M and again represent 1, 2, or 3, but Total 3, 4 or 5

, C X4 represents an oxygen atom, a sulfur atom, NRI2 (R12 represents a hydrogen atom "C 4 alkyl, phenyl (arbitrarily substituted with a halogen atom, hydroxyl, Cl ~ C4 alkoxy))), or R3 and R4 together (CH2) nZC (= Υ) (η means 2, 3 or 4, ζ, Υ has the same definition as above)]. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, followed by the compound (1 ) Each substituent. In the present specification, "η-" means positive, "i" means different, "t-" means third, and "c-" means a ring. "Me" represents methyl, "Et" represents ethyl, "Pr" represents propyl, "Bu" represents butyl, "Pen" represents pentyl, "Hex" represents hexyl, and "Ph" represents phenyl. Examples of R1 and R2 can be hydrogen atoms. Me, E t, n- pr, and the paper size apply Chinese National Standard (CNS) A4 specification (210.X 297 mm) 85 · 3 · Amendment A7 B7 Central Standard of Ministry of Economic Affairs Printed by the Consumer Cooperative of the Bureau — Μ t • V »< · V. Description of the invention () 1 Supplementary allowance 1 i — Pra η Β U, i — B u > S e C — B u and t — 1 1 | BU o And R 1 and R 2 together become (C Η 2) 4 or (c H 2) 5 Examples of 1 I formed as a spiral ring 0 Please 1 1 First 1 A has 0 Η > 0 c (〇) Μ e > 0 C (0) E t, read back 1 1 0 C (0) — n — ρ r > 0 c (0) — \ — P r 1 of surface I Note 0 C (0) n Β u > 0 c (〇) BU and other matters of interest 1 I 0 C (0) se C — B u, 0 C (O) t B uo Please fill in this package again. —Indicates single-bond bond O Page 1 X Example of oxygen atom> Sulfur atom, C (0) > C (S) > 1 IN Η > NM e, Ν Ε t, Ν-η — Pr — N — i — P r, 1 1 IN — C -P r > Ν — η — Β u > Ν — 1 — BU > 1 1 order N _sec — BU > Ν — t — Β U and other examples of O 1 R 3 and R 4 include a hydrogen atom, M e , E t, n — P r > 1 i — P r, c — Pr > n — Β U > i — B u, 1 1 S ec — B u > t — Β u, η — Ρ en, c — P en, 1, 4¾ η — H exc — Η e X, P h > benzyl p-chlorobenzyl, I p-fluorobenzyl > p-bromobenzyl, phenethyl, P-chlorophenethyl, p-fluorobenzene 1 1 I ethyl > p-bromophenethyl, c H 2 C 0 2 Η > c H 2 C 0 2 M e > 1 _ 1 1 C Η 2 C 0 2 E t > (c H 2) 2 C 0 2 Μ € ', 1 1 (CH 2) 2 C 0 2 Ε t, (C Η 2) 2C Η (0 M e) 2, 1 1 (CH 2 ) 2 C Η (〇Ε t) 2, 1 1 (CH 2) 3 〇Η (CH 2) 3 0 M e (C Η 2) 3 0 E t 1 I (C Η 2) 3 C 1 > ( C Η 2) 3 Β r (C Η 2) 3 F, 1 1 I (c H 2) 3 C 〇2 Η, (CH 2) 3 C 0 2 M e, 1 1 CNS) Α4 specification (210.X297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 8'5. March 3rd-7th Amendment 5. Invention Description (1) (C Η 2) 3 c 0 2 E t, CH) 3C H (Μ e) 2, (C Η 2) 3 c H (E t) 2, C (0) 0 M e, C (0) 0 E t, C (0) 0 n -P r, C (〇) 0 — i — P r C (〇) 0 — c — Pr > C (0) 0 — n — B uc (0) 0 — i — Β u, C (0) 0 — sec — BUC (0) 0 — t — BU, C (0) 0 — n — P en C (0) 〇 — C — P en, C (0) 0 — n — H e X > c ( 0) 0 — C — H ex, C (0) 0 (c H 2) 2 c 1, C (0) 0 (CH 2) 2b r > C (0) 0 (CH 2) 3 c 1 > C (0) 0 (c H 2) 3 B r > c (0) 0 ρ h > C (0) 0 c H 2] P h > C (0) NHM e, C (0) NHE t, C (0) NH — n — P r, c (0) N Η — i-P Γ Λ C (0) NH-c — P r, c ( 0) N Η — η — B u, C (0) NH — i — B u, c (0) N Η — sec —B u > C (〇) NH — t — BU, C (0) Ν Η — N — P en, C (0) NH — c — P en > C (〇) NH — n — H e X, c (〇) Ν Η — c-He X > C (〇) NH (c H 2) 2 c C (0) NH (c H 2) 2 B r > C (0) NH (c H 2) 3 C 1 > C (0) NH (c H 2) 3 B rc (〇 ) Ν Η P h > C (0) NHGH 2F h, C (0) NHC (0) CC 3 (Please read the precautions on the back before filling out this page) This paper size applies Chinese National Standard (CNS) A4 specifications (210.X297 mm)-Binding and ordering A7 B7 3, -7 Amendment Supplement V. Invention Description (? ), C (S) NHMe, C (S) NHEt, C (S> NH— n-Pr, C (S) NH— i-Pr, (Please read the precautions on the back before filling this page) C (S ) NH-c-Pr, C (S) NH-n-Bu, C (S) NH-i- Bu, C (S) NH-sec- Bu, C (S) NH- t-Bu, C (S ) NH- n-Pen, C (S) NH-c- Pen, C (S) NH-n-Hex, C (S) NH- c- Hex, C (S) NH (CH2) 2C1, C (S ) NH (CH2) 2Br, C (S) NH (CH2) 3C1, C (S) NH (CH2) 3Br, C (S) N Η Ph, C (S) NHCH2Ph, C (N — CN) NHMe, C (N-CN) NHBt, C (N — CN) NH-n-Pr, C (N-CN) NH-i-Pr, C (N-CN) NH-c-Pr > C (N-CN ) NH-n-Bu > C (N-CN) NH- i-Bu, printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy, C (N-CN) NH- sec-Bu, C (N-CN) NH- t -Bu > C (N — CN — NH-n-Pen, C (N-CN) NH-c-Pen > C (N-CN) NH-n-Hex, C (N-CN) NH- c-Hex > C (N-CN) NH (CH2) 2C 1. This paper size is applicable to China National Standard (CNS) A4 specification (2IQX297 mm)

A7 85. 3 .-7 repair ilL __ ^ _ B7__ is a a. 5. Description of the invention () L === —- ™ C (N-CN) NH (CH2) 2Br, C (N — CN) NH (CH2) 3C1, C (N-CN) NH (CH2) 3Br, C (N-CN) HNPh > C (N-CN) NHCH2Ph or R3 and R4 together with the N atom combined with these represent the following Q1 ~ Q3 6. (Please read the precautions on the back of this page and fill out this page first.) Binding. Order.1 Printed on the paper by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The paper size applies to the Chinese National Standard (CNS) A4 specification (21QX 297 mm) (9) ON—ύίΓΧΝ—

丨 Q2 ph

6Q Q7 A7 B7 ^ —Q4 ^^ \ Ν 丨 φ 'NIQ3 ^ Ι ^ Ν— φ ph

AM

e

OH .N—Q5IN—

Q (Please read the notes on the back before filling this page)

OH

'N—Ql

N- ph 2 Q1 3 Q1 4Ql ph

Printed by the staff of the Central Standards Bureau of the Ministry of Economic Affairs F Cooperative N 丨 Qlhn n—Q2 6 ph

7 e / 〆 niqim-nn- Q22

Qlo〆, NI 5 8 h / 〆Q1P-.N, N- 9 Q1 20

3 2Q N—Q24 oNHX ΓΝΙ Q25 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3. 10,000 12 A7 B7 V. Description of the invention (/ &)

Q27

• Me Factory M,. Factory NH (n 乂 ο, 乂 S

NCN Q30 Q28 Q26

Ν 人. people. Q29

Q34 Q35 Q33 (Please read the precautions on the back before filling this page)

• Q36

* Ν NCN

I

* 1T Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the present invention is a pharmaceutical composition capable of enhancing myocardial contractility and reducing heart beats, which contains the compound represented by the following formula (II) Optical isomers of asymmetric carbon atoms at the quaternary position, or those which can form pharmaceutically acceptable compounds as effective ingredients,

RlU6

(ID [where X6 is not present or represents an oxygen atom; this paper size applies to the Chinese national standard (milk) 8 4 specifications (210 '/ 297 mm) 5. Description of the invention (A7 B7 Assist. 3 ·-* 1 Modification-year, month and year », nitrogen atom (this nitrogen atom may be replaced by a hydrogen atom X 5 represents an oxygen atom); A 1 represents a hydrogen atom represents a CC 4 alkyl group; B 1 represents a hydrogen atom; R 13 And R 14 may be the same or different from each other and represent a hydrogen atom or a C i ~ C 4 alkyl group; R 15 and R 16 may be the same or different from each other and represent a hydrogen atom; the alkyl group of C i ~ Cs {The alkyl system may Optionally substituted by hydroxy, Cl ~ c4 alkoxy or phenyl) or C (^ Y1) represents an oxygen atom, sulfur atom or N-CN, Z1 represents nr20 (R2〇 represents a gas atom, an alkyl group ), Rw is a hydrogen atom, or R15 and R · 16 together represent 1,4-butylene or 1,5-pentyl (the butyl or pentyl group may be optionally substituted with a fluorenyl group, respectively), Or R1S and R16—. (CH2) 〇X7 (CH2) p (0 and p represent 1, 2, or 3 respectively, but the total is 3 or 4, X7 represents an oxygen atom, via a radical or 〇C (〇 ) R17 (R17 series (please read first Note on the back, please fill in this page again) Packing. Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (R23 represents phenyl), or R15 and Rw together represent _ (CH2) 3NHC (0)-)] ° This invention A pharmaceutical composition capable of enhancing myocardial contractility and reducing heart beats. In formula (II), R15 is a hydrogen atom and R16 is C (= Y2) NHR24 (Y2 represents an oxygen atom, a sulfur atom, or N-CN, R24 represents phenyl, benzyl or a branched alkyl group which may be Ci ~ C8

NR 2 3 The medicine group of the present invention which can enhance the myocardial contractility and reduce the number of beats of the heart is applicable to the Chinese National Standard (CNS) A4 specification (21QX297 mm) 5. Description of the invention (A7 B7 85. 3.-7 — The Γ compound is added in the year and month, and R15 and R16 in formula (II) together represent (CH2) k NHC (= Υ 3) (where k represents 2, 3 or 4, and Υ 3 represents an oxygen atom, a sulfur atom, or N — CN). The pharmaceutical composition of the present invention capable of enhancing myocardial contractility and reducing the number of heart beats, wherein R15 and R16 of formula (II) are Ci ~ c6 alkyl groups. The present invention can enhance myocardial contractility and reduce heart A pulse composition of a pharmaceutical composition, wherein R15 and R16 of formula (II) together represent (CH2) 4 or (C Η 2) 5. Examples of the compounds of the present invention are shown below, and X 1 and X 2 are absent. Also, Ci'Ti is as defined above. Qn == (R 3 —) (R4 —.) N—0 means (Please read the precautions on the back before filling this page.) Installation. Order the central standard of the Ministry of Economy Bureau employee consumer cooperatives printed

CD The size of this paper applies the Chinese National Standard (CNS) A4 specification (210.X297 mm) 1 u-A7 B7 V. Description of the invention (11) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs [Table 1] Table 1 ( Continued) NoX X1 X2 AB R1 R2 R3 R4 1 0 ― 〇OH H Me Me E t Et 2 〇 ― OH H Me Me (R3-) (R4-) N = Q8 3 0 ― ― OH H Me Me (r3-) (R4—) N = Q 8 4 〇― — OH H Me Me (R3-) (R4-) N = Q 1 5 〇- ― OH H Me Me H Me 6 〇― OH H Me Me H CH2Ph (pF) 7 〇—-OH H Me Me H CH2Ph 8 〇- OH H Me Me Me CHsPh 9 〇—-OH H Me Me H n — H ex 10 〇 ― OH H Me Me (r3-) ( R4-) N = Q2 2 11 〇- ― OH H Me Me (R3-) (R4-) N = Q2 1 12 〇 ― ― OH H Me Me (r3-) (R4--) N = Q2 3 13 〇- -OH H Me Me (r3-) (R4-) N = Q 1 7 14 〇- ― OH H Me Me (R3—) (R4--) N = Q1 9 15 〇--OH H Me Me (r3-) (R4-) N = Q2 0 16 〇 ~ ~ OH H Me Me H (CH2) 3〇Me 17 〇--OH H Me Me H (CH2) 3C02E t 18 〇 ― OH H Me Me HC H2C O2E t 19 〇- ― OH H Me Me H (CH 2) 3C 1 2 0 〇--OH H Me Me H (CH2) 2〇h 2 1 〇--OH H Me Me HH 2 2 〇--OH H Me Me HC (O) NHMe 2 3 〇--OH H Me Me HC (S) NHMe ---------- Pack-(Please read the precautions on the back before filling this page) The size of the paper is applicable to China National Standard (CNS) A4 (210 X 297) 83. 3. 10,000 14 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, 'Invention Description (12) 1 I [Table 2] Table 1 (Performance) 1 1 1 No * X X1 X2 AB R1 R2 R3 R4 1 / -— V Please 1 1 2 4 〇— — OH H Me Me HC (0) NHPh Read 1 2 5 〇—OH H Me Me HC (O) NHC (O) CC12 Back I 1 2 6 〇— — OH H Me Me HC (〇) NH (CH2) 3C 1 Note 2 7 〇- — OH H Me Me HC (〇) NH (CHa) sC 1 Matter 1 I 2 8 〇 — — OH H Me Me HC (0) NH (CH2) 2C 1 Filled 1 2 9 0 — — OH H Me Me HC (0) OE t Maben. Page 3 0 〇 一 — OH H Me Me HC (0) 0 (CH2 ) 2C 1 ^^ 1 3 1 〇- — OH H Me Me (R3—) (R4-) N- = Q2 6 1 I 3 2 〇— — OH H Me Me (R3—) (R4-) N-Di Q2 5 '1 3 3 〇 一 — OH H Me Me HC (0) NH-c-He x 1 Order 1 3 4 〇 -— OH H Me Me HC (0) NH-t-Bu 3 5 〇— OH H Me Me HC (O) OMe 1 | 3 6 〇— — OH H Me Me HC (S) NH—t—Bu 1 3 7 〇— — OH H Me Me (R3—) (R4—) N — = Q3 1 1 I 3 8 〇 一 — OH H Me Me HC (0) 0 (CH2) 3C 1 3 9 〇—-OH H Me Me (R3—) (R4—) N — = Q3 2 1 | 4 0 〇—-OH H Me Me Et E t I 4 1 〇— — OH H Me Me E t E t I | 4 2 〇—- OH H Me Me E. E t-I 4 3 〇 一 — OH H Me Me (R3—) (R4 —) N-Di Q 8 I 4 4 〇— — OH H Me Me H (CH2) aCH (OE t) 2 I 4 5 〇— — OH H Me Me (R3—) (R4—) N- = Q 2 III 1 1 1 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 83.3 10,000 15 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention ([Table 3] 13) Table 1 (continued) 1 1 1 1 No · X X1 X2 AB R1 R2 R3 R4 —s Please first Read 1 1 .1 4 6 〇— — OH H Me Me H (CHz) 3CO2H 1 4 7 〇— — OC (0) Me H Me Me HH Back | 4 8 0-OH HE t E t (R3—) (R4-) N -= Q 8 meaning 1 4 9 〇 — — OH H Et E t HH Filial item 1 I 5 0 〇 — — OH HE t E t HC (O) NHMe Fill again g 5 1 〇 — — OH H Et Et HH I 5 2 〇— OH H Me Me HC (N-CN) NH-t-Bu > — ^ 1 5 3 NH — — OH H Me Me (R3—) (R4—) N — = Q8 1 | 5 4 NH — — OH H Me Me (R3—) (R4—) N_ = Ql 1 5 5 NH — — OH H Me Me E t E t 1 Order 1 5 6 S — — OH H Me Me (R3 —) (R4-) N- = Q 8 5 7 S-— OH H Me Me (R3—) {R4—) N ~ — Q 1 1 | 5 8 S — — OH H Me Me Et E t 1 5 9 〇— — OH H Me Me (R3—) (R4—) N-Di Q3 1 | 6 0 〇— — OH H Me Me (R3—) (R4-) N- = Q4 〇6 1 〇— — OH H Me Me (R3—) (R4-) N- = Q5 1 | 6 2 〇— — OH H Me Me (R3—) (R4—) N — = Q6 1 6 3 〇—-OH H Me Me (R3— ) (R_4_) N —Two Q7 1 | 6 4 〇 — — OH H Me Me (Rs—) (R4-) N- = Q9 ·-1 6 5 〇 — — OH H Me Me (R3—) {Ra ~) n- = qi 0 1 I 6 6 〇— — OH H Me Me (R3—) (R4-) n- = q 1 1 1 6 7 〇- — OH H Me Me (R3—) (R4-) N-II Q1 2 1 1 1 1 1 This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 83. 3.10,000 -16-A7 B7 V. Invention Explanation (14) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs [Table 4] Table 1 (缜) No · X X1 X2 AB R1 R2 R3 R4 6 8 〇— — OH H Me Me (Rs—) (R4- ) N- = Q1 3 6 9 〇— — OH H Me Me (R3—) (R4-) N- = Q1 4 7 0 〇— — OH H Me Me (R3—) (R4-) N-Di Q1 5 7 1 〇— — OH H Me Me (R3—) (R4-) N- = Q1 6 7 2 〇 一 — OH H Me Me (R3-) (R4-) N- = Q1 8 7 3 〇--OH H Me Me (R3—) (R4—) N —Two Q2 4 7 4 〇— — OH H Me Me (R3—) (R4-) N- = Q2 7 7 5 〇— — OH H Me Me (R3— ) (R4-) N- = Q2 8, 7 6 〇—-OH H Me Me (R3—) (R4-) N- = Q2 9 7 7 〇— — OH H Me Me (R3—) (R4-) N- = Q3 0 7 8 〇— — OH H Me Me (R3—) (U N- = Q3 3 7 9 〇— — OH HM e Me (R3—) (R4-) N — = Q3 4 8 0 〇- — OH H Me Me (R3—) (R4-) N- = Q3 5 8 1 〇—-OH H Me Me (R3—) (R4-) N- = Q3 6 8 2 〇 — — OH H Me Me Me Me 8 3 〇 — — OH H Me Me nP rn — P τ 8 4 〇 — — OH H Me Me i -P ri ~ Pr 8 5 〇- — OH H Me Me cP rc — P r 8 6 〇— — OH H Me Me n —B ub — B u 8 7 〇— — OH H Me Me 1 —B ui —B u 8 8 〇— — OH H Me Me sec —Bu sec-Bu 8 9 〇 一 — OH H Me Me t — B ut — B u (Please read the precautions on the back before filling this page)

The size of the paper used in the I edition applies to the Chinese National Standard (CNS) A4 (210X297 mm) 83. 3. 10,000 17 A7 B7 V. Description of the invention (15) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs [Table 5 ] Table 1 (continued) No · X X1 X2 AB R1 R2 R3 R4 9 0 〇 — — OH H Me Me n —P en η — P en 9 1 〇 — — OH H Me Me n —H exn —H ex 9 2 0 one — OH H Me Me c one P enc — P en 9 3 〇 — — OH H Me Me c — H enc — H ex 9 4 0 — — OH H Me Me Ph Ph 9 5 〇 — — OH H Me Me CHsPh CH2Ph 9 6 〇-— OH H Me Me HC (S) NHE t 9 7 〇 — — OH H Me Me HC (S) NH-n-Pr 9 8 〇 — • — OH H Me Me HC (S ) NH-i-Pr 9 9 〇- — OH H Me Me HC (S) NH-c-Pr 10 0 0 — — OH H Me Me HC (S) NH-n-Bu 10 1 〇 — — OH H Me Me HC (S) NH-i-Bu 10 2 〇 — OH H Me Me HC (S) NH-s e c-Bu 1 0.3 〇 — — OH H Me Me HC (S) NH-n-Pen 10 4 0 — — OH H Me Me HC (S) NH-c-Pen 1 0 5 〇 — — OH H Me Me HC (S) NH-n-He x 10 6 〇 — — OH H Me Me HC (S) NH -cH ex 10 7 〇— — OH H Me Me HC (S) NHPh 10 8 〇— — OH H Me Me HC (S) NHCHsPh 10 9 〇- mono-OH H Me Me HC (N-CN) NHMe 110 〇--OH H Me Me HC (N-CN) NHE t 111 〇 — — OH H Me Me HC (N-CN) NHE t (Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 83. 3. 10,000 18 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (16) [Table 6] Table 1 (Performance)

No · X X1 X2 AB R1 R2 R3 R4 112 〇 一 — OH H Me Me HC (N-CN) NH-nP r 113 〇 一 — OH H Me Me HC (N-CN) NH-i-Pr 114 〇 一— OH H Me Me HC (N-CN) NH-c-Pr 115 〇—-OH H Me Me HC (N-CN) NH-n-Bu 116 〇 一 — OH H Me Me HC (N-CN) NH -i-Bu 117 〇 一 — OH H Me Me HC (N-CN) NH-s e c-Bu 118 〇-- OH H Me Me HC (N-CN) NH-nP en 119 〇 one-OH H Me Me HC (N-CN) NH-cP en 12 0 〇 一一 OH H Me Me HC (N-CN) NH-n-Hex 12 1 〇- — OH H Me Me HC (N-CN) NH-c- Hex 12 2 〇- — OH H Me Me HC (N-CN) NH-Ph 12 3 〇- -OH H Me Me HC (N-CN) NH-CHzPh 12 4 〇- — OH H Me Me Me n —P r 12 5 〇 一 — OH H Me Me E t η —P r 12 6 〇—-OH H Me Me n — P rn —B u 1 2 7 〇 一 — OH H Me Me n — P rn —P en 12 8 0--OH H Me Me n — P rc —P en 12 9 〇--OH H Me Me E t η-H ex 13 0 0--OH H Me Me E t Ph 1 3Ί 〇-OH H Me Me n — P r CHsPh (Please read the notes on the back before filling (Page) This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 83. 3. 10,000 -19-A7 B7 V. Description of the invention (17) The compound provided to the present invention is in the third position of the piperan ring The optically active body having an asymmetric carbon atom at the 4-position, and having the asymmetric carbon, can also be used in the application of the present invention as the racemic body. Further, stereoisomers at the 3 and 4 positions of the piperane ring can also be used. In addition, when it is a compound capable of forming a hydrazone, the pharmaceutically acceptable hydrazone can also be used as an active ingredient. Next, a method for producing the compound to be used in the present invention will be described. In the compound represented by general formula (I), X is an oxygen atom, and neither R nor R4 is C (= Y). For ZR6, as shown in the following reaction formula, the compound represented by formula (3) and the formula ( 4) The compound shown can be prepared by reaction. When A is 0Η by formula (5), a single bond is represented by A and B from formula (6). (Please read the precautions on the back before filling this page)

、 1T Consumption cooperation of employees of the Central Standards Bureau of the Ministry of Economic Affairs

h 的 The solvent used for the reaction of compound (3) and compound (4) can be-this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3. 10,000 -20-employees of the Central Bureau of Standards, Ministry of Economic Affairs Printed by the Consumer Cooperative A7 _______ B7 _._ '_ V. Explanations (j is as follows. There are sub-fluorene-based solvents represented by toluene 5E sulfone, represented by dimethylformamide or dimethylacetamide Ammonium solvents, ether solvents represented by diethyl ether, dimethoxyethane, or tetrahydrofluorene, and alcohol solvents represented by methanol, ethanol, or isopropanol. Among them, alcohol solvents are preferred. The reaction temperature is usually from ice-cooling to the reflux temperature of the reaction solvent used, preferably the reflux temperature of the solvent used. Sometimes the reaction is carried out under pressure with a mole ratio compound (4) / compound ( 3 Γ (Mohr ratio) is in the range of 0.5 to 2.0, which is more in the range of 1.0 to 1.1. It can be obtained that any compound represented by formula (5) or formula (6) is reacted as described below. The conditions or the processing conditions after completion of the reaction are different. The compound represented by the formula (6) In tetrahydrofuran, it can be prepared by reacting a compound represented by the formula (3) with a compound represented by the formula (4) in the presence of sodium hydride. However, depending on the reverse conditions (reaction time, reaction temperature, etc.), it can also be obtained. To the compound represented by formula (5 '). Moreover, dehydration may be induced due to different post-treatment methods. For example, if an acid or alkali is present in the reaction solution, these acids are not removed by water washing during the post-treatment. Or base, and sometimes it can be dehydrated when directly heating and concentrating the reaction solution. However, the dehydration conditions are often affected by the type of compound, reaction conditions, and post-treatment conditions. In the compounds provided to the present invention, X is an oxygen atom, and R3 or Any one of R4 is C (= Y.) Z > R 6 can follow the following reaction formula, and apply the Chinese National Standard (CNS) A4 specification (210 > < 297 mm) on the paper size as follows: 83. 3.10 , 000 -21------, L ----- " / V ------- Order ----- ^-At'v (Please read the notes on the back before filling in this Page) A7 B7 V. Description of the invention (19) A compound represented by the reaction formula (3) and a compound represented by the formula (7) in a solvent are converted to the formula (8) Was then formula (8) is reacted with R Y C N 6 should

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Anti 6 R 2 〇C DEK ie 9 or Wuhe Diaosuo (#xiange read the note on the back of the book, write this page) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 83. 3. 10,000 This paper size applies China National Standard (CNS) A4 specification (210X297 mm) -22-A7 B7 V. Description of invention (2)

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2) ο. 9 proton N proton N iodine (., Proton) represents the original ester of bromobenzene Z, a, and lactic acid. The original sulphur chloride or formula is shown, the transepiester is benzene W 9 proton or Protonic oxygen or acid sulfonate, ester-based alkyl low-acid sulfonate ring can be described in a simple way., The intermediate ring which is the raw material and the original material is the compound of the intermediate. Guan R4 2 and 1 Ming F 1 R R {This type of 3 / \ is printed by the staff of the Central Bureau of Standards of the Ministry of Economy

Κ! Ε2 (3) [In the formula, R1 and R2 are the same as defined in the formula (I)], and the compound can be prepared by the following method. The whole process is shown in the following flow chart. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 83.3. 10,000 -24-(Please read the precautions on the back before filling this page)

V. Description of the invention (22) Μ B7 0

2) (Please read the notes on the back before filling in this page) Order Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ^ & 〇) dbcn

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Take sodium hypochlorite (NaOC

[Wherein R1 and R2 are the same as defined in the formula (I)], and make it a compound represented by the formula (3) without X1 and X 2 being an oxygen atom (compound 3 (X1 ^ —, X2 = 0), this compound can be reacted with a reducing agent represented by sodium nitride or triethyl phosphite (P (OE t) 3), etc., which has the ability to remove oxygen in the N-oxygen ion type. 'A compound represented by formula (3), which does not have X 1 and X 2 (compound 3 (X ^ X2: ^-)). Also, about 1 equivalent of a suitable peracid (for example, m-chloroperbenzene) Formic acid, hydrogen peroxide, and peracetic acid are the same as the following) When compound 3 (X1, X2 = —) is treated, a compound represented by formula (3) can be obtained, and χι is an oxygen atom without X2 ( Compound 3 (χι = 〇, χ2 = _)). In this case, if a peracid of 1 equivalent or more is used, a compound represented by formula (3) can be obtained, and X1 and X2 are both oxygen compounds (compound 3). (1 2) The compound shown can be prepared according to a known method (for example, it can be prepared by referring to the factory with -em., 2X, 1127 (19 8 7)). Compound 3 (χι = 0, χ2 = _) also Can use Sodium chlorate treatment type (1 4) The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) Q ------, 玎 ------- 0 "(please read the back first Please note this page before filling in this page) Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 83. 3. 10,000 -26-Α7 Β7 V. Description of Invention (24)

---------- τι--, 'if' (Please read the notes on the back before filling this page) (14) [In the formula, R 1 and R 2 are defined by formula (I) Same) The compounds shown can also be prepared. The compound represented by the formula (14) can be produced by a known method (the above-mentioned literature). The solvent used in the reaction of the compound (8) with the formula Y = C = N-R6 or C 1 C (0) OR6 may be the following. Asian-based solvents represented by dimethylarsine, amines based on dimethylformamide or dimethylacetamide, ethers represented by diethyl ether, dimethoxyethane, or tetrahydrofuran Solvents, and dichloromethane and chloroform-based solvents, especially halogen-based solvents are preferred. The reaction temperature is usually from ice cooling to the reflux temperature of the reaction solvent used, and preferably the reflux temperature of the solvent used. Sometimes under pressure. Moore ratio compounds (8) / Y = C = NR6 or C 1 C (〇) 〇R 2 compounds (Moore ratio) printed by the consumer cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. ) Is in the range of 0.5 to 2. 0, preferably 1. 0 to 1.1 range. In the compound of the present invention represented by the formula (I), if X is a sulfur atom or a nitrogen atom (which may be substituted by a hydrogen atom or a Ci ~ C3 fluorenyl group), the compound represented by the formula (15) can be obtained through a 3 or 4 process. synthesis. The compound of formula (15) is transformed into the formula. (17) The compound is known, for example, it can be used to pick him up by using solid-solid gold after the skin secret, / " 'KTC' \ i & gt J ·. , H. /,. A.. «Λβ \

3 Received VN 83. 3. 10,000 '27-Cooperative production of A7 B7 by staff of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of Invention (25) JP 56-57785 and JP 56-122380 The method can be achieved. The compound of formula (17) can be in an aqueous solution in the presence of inorganic acids such as osmic acid, sulfuric acid, or organic acids such as acetic acid. After the general diazotization reaction represented by the method of reacting it with sodium nitrite, 1 0 0 ° C is preferably heated at 50 to 100 ° C to close the ring, which can be synthesized into the formula (18) where X is a nitrogen atom. A and B together represent a single bond. The compound may be produced by heating only the compound of formula (18), so it may be prepared during the synthesis reaction of formula (18) or after the synthesis. Further, an anhydride such as benzoic anhydride or acetic anhydride or a base such as potassium carbonate can be used to dehydrate it, or it can be synthesized. When X of the formula (I) is an alkylamine group, the compound (18) or its dehydrated product can be reacted with diazomethane, or can be prepared by reacting with an alkyl halide in the presence of potassium carbonate. The compound of the formula (17) can be reacted with sulfinylanilide in an inert solvent such as benzene, toluene, xylene, dichlorobenzene and the like to synthesize the compound of the formula (20) in which X is a sulfur atom. The reaction temperature is at 5 to 120 ° C, preferably at 50 to 100 ° C. A and B together represent a single bond. The compound may be produced by heating only the compound of the formula (20). Therefore, it may be prepared during the synthesis reaction of the formula (20) or after the synthesis. Further, an anhydride such as benzoic anhydride or acetic anhydride or a base such as potassium carbonate can be used to dehydrate it, or it can be synthesized. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3.10,000 -----: ---- 〇 衣 ------ tT ------ `` 'T / _ \ (Please read the notes on the reverse side before filling out this page) -28-A7 B7 V. Description of the invention (2θ) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(Please read the precautions on the back before filling this page) The paper size is applicable to the Chinese National Standard (CNS) Α4 specification (210 × 297 mm) 83. 3. Order 10,000 -29-V. Description of the invention (27)

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§ s This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 83. 3. 10,000 A7 B7 V. Description of the invention (2δ) [In the reaction formula, the Z series represents (NR9). Or oxygen atom or sulfur Atom, W represents a chlorine atom, a bromine atom, a master atom, a lower alkyl sulfonate, a phenyl sulfonate, or a tolyl sulfonate] In the compound of formula (1 5), neither R3 nor R4 is C (= Y) ZR 6 and the compound represented by formula (2 4) (in this case, R 3 and R 4 do not contain C (= Y) ZR6), the compound represented by formula (2 3) and the compound represented by formula (4) can be made in an inert solvent. The compound can be prepared by reaction. The solvent used in the reaction of the compound (2 3) and the compound (4) may be the following. Subaerosol solvents represented by dimethylasco, amines based on dimethylformamide or dimethylacetamide, ethers represented by diethyl ether, dimethoxyethane or tetrahydrofuran Solvents, and alcohol solvents such as methanol, ethanol, or isopropanol. Among them, alcohol solvents are preferred. The reaction temperature is usually from ice cooling to the reflux temperature of the reaction solvent used, and preferably the reflux temperature of the solvent used. Mole ratio compounds (4) / compounds (3) (mole ratio) of reaction raw materials printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs may be pressurized at times ranging from 0.5 to 2.0. Best line 1. 〇 ~ 1.1 range. Among the compounds represented by formula (1 5), any one of R3 or R4 is C (= Y) ZR6 and the compounds represented by formula (2 6) and formula (2 7) can be respectively shown according to the above reaction formula, The compound represented by formula (2 3) and the compound represented by formula (7) are reacted in an inert solvent to obtain a compound of formula (2 5), and then the compound obtained by formula (2 5) and R6NCY (83. 3. 10,000 (please listen first Read the notes on the reverse side and fill out this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of invention (29)

RsNCO, R6NCS) or C1C02R6 to obtain a compound represented by formula (2 6) or (2 7). Compounds in which R 3 and R 4 form a ring together can be prepared by cyclizing a compound represented by the formula (2 8) according to the above steps. I ---- ： ----- Q Clothing II (Please read the precautions on the back before filling this page),-!!

The central standard bureau of the Ministry of Economic Affairs, Bei Gong Xiao F, Cooperative Society — The solvent used for the reaction of compound (25) with the formula Y = C = N_R6 or C 1 C (Y) OR 6 may be as shown below. Subaerosol solvents represented by dimethylasco, amines based on dimethylformamide or dimethylacetamide, ethers represented by diethyl ether, dimethoxyethane or tetrahydrofuran Solvents, and halogen-based fluxes represented by dichloromethane and chloroform. Among them, a halogen-based solvent is particularly preferable. The reaction temperature is usually from ice cooling to the reflux temperature of the reaction solvent being thrown, and preferably the reflux temperature of the solvent used. Moore ratio compounds (2 5) / Y = c = NR 6 or C 1 C (0) 0 R 2 compounds (Mohr ratio) may be reacted under pressure from 0.5 to 2. A range of 0, preferably a range of 1.0 to 1.1. This paper size applies to China National Standard (CNS) A4 (210X297 mm) 83.3.10,000

X

(31) A7 B7 V. Description of the invention (30) Among the compounds of the present invention represented by formula (I), if A is a fluorenyl group, the formula can be shown in the following reaction formula in an inert solvent in the presence of a suitable base ( 30) can be prepared by reacting the compound shown with a chelating agent. The solvent used for the χΐ Ν into R2b (30) reaction can be as shown below. Asian-based solvents represented by dimethylarsine, amines based on dimethylformamide or dimethylacetamide, ethers represented by diethyl ether, dimethoxyethane, or tetrahydrofuran Solvents, and halogen-based fluxes represented by dichloromethane and chloroform, can also react without solvents. The base used in the reaction may be triethylamine, pyridine, diisopropylethylamine, DBU (diazacycloundecene), and the like. The hydrating agents include fluorenyl chloride, fluorenyl bromide and the like, or anhydrides. The reaction temperature is usually from ice-cooling to the reflux temperature of the reaction solvent used. Mole ratio of the reaction raw material is 0.5 to 2.0 for compound 30, and preferably 1.0 to 1.1. Among the compounds of the present invention represented by formula (I), R4 is NC (N — CN) NHR 9 and can be reacted by formula (32) with carbodiimide in an inert solvent as shown in this reaction. Applicable to China National Standard (CNS) A4 specification (210X297 mm):. ^,-(谙 Please read the notes on the back before filling in this Jc, τ Printed by the Central Consumers ’Bureau of the Ministry of Economic Affairs, printed by the Consumer Goods Cooperative 83. 3. 10,000 33 V. Description of the invention (31) R3, χΐ NHR9

Α7 Β7

⑴-Η # ----— (2) H2N-CN

(33)

0) -h2s (2) H2N-CN

(35) The consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China printed 11 and then applied dehydrogen sulfide, and then reacted with cyanamide to obtain the compound represented by formula (3 3). R3 and R4 together form a cyclic thiourea compound represented by the formula (3 3 4). The same conditions can be used to guide the compound represented by the formula (3 5). When synthesizing the optically active substance represented by the formula (I) to be provided in the compound of the present invention, a method of optically dividing the racemate can be used (Japanese Patent Application Laid-Open No. 1 2 8 6, US Patent No. 5 0 7 0 3 7 , European Patent No. 4 0 9 1 65) or an asymmetric synthesis method (Japanese Unexamined Patent Publication No. 5-30 0 8 8 8 and European Patent No. 5 3 5 7 7). As mentioned above, the present inventors have found that the compound represented by formula (I) is equipped with ---------------... (Please read the precautions on the back before filling in this page ) This paper size applies the Chinese National Standard (CNS). Α4 size (210x297 mm) 83. 3. 10,000 34-Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ________B7 _._ V. Description of the invention (32) With strength Increased myocardial contractility and reduced heart beat. The compound of the present invention, which does not have a heart-suppressing effect, but has an increase in cardiac contractility, has a strong heartbeat reduction effect in the same amount as a heart-strengthening effect. Reduced myocardial oxygen consumption according to this effect can reduce myocardial motion The burden shows an anti-arrhythmic effect, and it also has an anti-arrhythmic effect because it can prolong the effective anti-diarrhea period. For this reason, the compounds related to the present invention are expected to be very useful for the treatment of cardio-vascular diseases and for the treatment mainly for reducing the heart beat beats in consideration of the heart-related oxygen consumption or energy consumption or metabolism. For example, it can be used as an anti-cardiac insufficiency agent for mammals including humans, or as a therapeutic agent for cardiovascular diseases caused by cardiac insufficiency, such as a therapeutic agent for ischemic heart disease, a therapeutic agent for hypertension, and an antibody fluid retention agent. , Pulmonary hypertension treatment agent, Membrane disease treatment agent, Congenital heart disease treatment agent, Myocardial disease treatment agent, Pulmonary edema treatment agent, Laborer heart pain treatment agent, Myocardial infarction treatment agent, Antiarrhythmia agent, Antiatrial fibrillation agents are extremely useful. The present invention provides a pharmaceutical composition comprising a compound represented by the formula (I) in a therapeutically effective amount. The administration forms of the compounds of the present invention may be parenteral injections (subcutaneous, intravenous, intramuscular, intraperitoneal injection), softening agents, suppositories, aerosols, or tablets, gums, granules , 'Tablets, sugars, liquids, emulsions, suspensions, etc. are administered orally. The above pharmaceutical or veterinary composition containing the compound of the present invention is about 0.1 to 99.5%, preferably about 0.1 to 30% by weight of the entire composition. The compound of the present invention. In the compound of the present invention or the composition containing the compound, the paper size is also applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3. 10,000 -35-!;-J ---- --- Order ------ OI (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Procurement Bureau of the Ministry of Economic Affairs A7 _B7 ___ V. Description of the invention ( 33) To contain other pharmaceutically or veterinary active compounds. These compositions may further contain a plurality of compounds related to the present invention. The clinically administered amount of the compound provided by the present invention varies depending on age, weight, patient sensitivity, degree of symptoms, etc., but usually the effective dose is 0.003 ~ 1.5 g per day for adults, compared with佳 系 〇 〇1 ～ 0. 6g or so. However, if necessary, an amount outside the above range may also be used. 0 The compound provided to the present invention can be prepared into a dosage form by conventional pharmaceutical methods. That is, tablets, capsules, granules, tablets for oral administration use excipients, such as sugar, lactose, glucose, starch, mannose, sugar alcohol; binding agents, such as hydroxypropyl fiber, syrup, and gum arabic , Animal gum, sorbitol, tragacanth, methyl cellulose, polyvinylpyrrolidone; disintegrating agents, such as starch, carboxymethyl cellulose or its calcium, microcrystalline cellulose, polyethylene glycol Lubricants, such as talc, magnesium or calcium stearate, silica; lubricants, such as sodium laurate, glycerol, etc., are prepared. Injectables, liquids, emulsions, suspensions, syrups and aerosols can be used as solvents for active ingredients, such as water, ethanol, isopropanol, propylene glycol, 1,3-butanediol, polyethylene glycol; surfactants , Such as sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ethers of hydrogenated castor oil, phospholipids; suspension agents, such as carboxymethyl sodium phosphonium, Cellulose derivatives such as methyl cellulose, tragacanth, and natural rubbers such as arabic rubber; preservatives such as parabens, benzyl ammonium chloride, and rhenium adipate. This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 83. 3.10,000 -36-(Please read the precautions on the back before filling this page-)

Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Zhengong Xiao F Cooperative A7 B7 ___ V. Description of the invention (34) For soft incubation of percutaneous absorption preparations, for example, white petrolatum, flow stone tincture, tincture alcohol, polyvinyl glycol Softening, hydrophilic softening, water-based gel base, etc. Suppositories can be prepared using, for example, cocoa butter, polyethylene glycol, lanolin, fatty acid triglycerides, cocoa coconut oil, polysorbate, and the like. Hereinafter, embodiments of the present invention are described in detail, but the present invention is not limited to those embodiments. [Synthesis example] The following shows a synthesis example of a compound which can be used for the medical use of the present invention. 0 Reference Example 1 Optically active 7,8-dihydro-6,6-dimethyl-1,8-epoxy-6H-piper Furo [2,3-f] phenylhydrazone-2,1,3-dioxadiazole at 3 0 Om | containing 4 Og (198 8 mmoles) 6,6-dimethyl-6H-piperano (2,3._f] Benzamidine-2,1,3-oxadiazole in dichloromethane solvent, 2. 4 g (3.7 millimoles) (foot, it) was added to [1,2 _Bis (3,5_di-tert-butylsalicylide amine) cyclohexane] manganese acetate (manufacturing method is described in Japanese Patent Application Laid-Open No. 5-5 0 7 6 4 5 and European Patent 5 2 1 0 9 Publication No. 9). Then add 1.2 j sodium hypochlorite aqueous solution (active chlorine 5%), adjust the pH to 11.3, and add 0.5N hydroxide while the paper is in accordance with Chinese national standards ( CNS) A4 specification (210X 297 mm) 83. 3. 10,000 (Please read the notes on the back before filling out this page) d. Order -37-Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A 7 B7 V. Invention Description (35) Aqueous sodium chloride solution. After stirring at room temperature for 10 hours, the stirring was stopped overnight. The reaction solution was extracted with chloroform (30 OmjXl, 20 Om 芡 X 1,50m and XI), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue of silica gel column chromatography (benzene: ethyl acetate = 5: 1) was re-submitted to silica gel column chromatography (benzene-benzene: ethyl acetate = 5: 1), and the resulting crystal was recrystallized with 60 ethanol to obtain 15 7 g (yield 3 6%) of the title compound. Optical purity > 9 9% ee. [Column: Chiral ce 1 1 (manufactured by Di ce 1 1 Chemical Co., mobile phase: hexane: isopriol = 4: 1, detection: UV254nm, flow rate: lmj ^ / 1 minute, column temperature of two 40 ° C, holding time of 9.2 minutes] Reference Example 2 Enantiomer use of the compound of Reference Example 1 (S, S) — [ 1,2_bis (3,5_ di-tertiary-butylsalicylide amine) cyclohexane] manganese acetate was synthesized with the reference example 1- 例 to synthesize the enantiomer of the compound of reference example 2 0.8 g (Yield: 4 8%), optical purity> 9 9% ee [holding time: 12.5 minutes] Synthesis Example 1 3 —Oxidation 7, 8 —dihydro-6, 6 — dimethyl — 7 — hydroxy — 8 — 2 Ethylamino-6H-piperano [2 3 — f] Benzene 1,2, 3, H Bisodiazole This paper size applies to China. National Standard (CNS) A4 specification (· 21〇 × 297 mm) 83. 3. 10,000 ------- --- 't-shirt-- > · ... \ J (Please read the precautions on the back before filling this page),-° -38-V. Description of the invention (36) A7 B7

Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and stirred at 40 ° C for 4 6 5mg (1.50 millimolar) 3,4 —dihydro-2,2 —dimethyl — 3 —hydroxyl — 4 — Diethylamino ~ 6-aminoamino-7-nitro- 2Η-phenylhydrazone [b] Pipeline, 102 mg (2.5 6 mmol) sodium hydroxide, 3 21115 ethanol, 6111 water, 0 . lmi? polyethylene glycol. To this solution was added 2.59 g (2.10 mmol) of 6% NaOCj? Aqueous solution and stirred for 15 minutes. The reaction solution was poured into water and extracted three times with ethyl acetate. Ethyl acetate was collected, washed with saturated food, and dried over anhydrous sodium sulfate. Silica column chromatography (solvent, ethyl acetate: hexane = 1: 2 (v / v)) was used to remove the residue after distilling off the solvent to obtain 189 mg (yield: 41%) of the labeled compound. Part of it is dissolved in ethanol. Adding HC and Et Η Η solution, and adding absolute ethanol, can obtain the wall crystal acid of the yellow crystalline labeled compound. Melting point: 160 ~ 164 ° C (decomposition) NMR (CDCj ^ s), tidal (ppm): 1. 1 5 (6 Η), 1 · 2 6 (3 Η), (. Please read the notes on the back before filling this page) t-shirts. The size of the paper is applicable to China Standard (CNS) A4 specification (210X297 mm) 83. 3.10,000 39-A7 B7 V. Description of the invention (37) 1 · 5 2 (3 Η), 2. 64-3. 14 (5Η), 3.56 (1 Η), 3. 8 5 (1 Η), 6. 5 7 (1 Η), 7. 3 0 (1 Η). Synthesis Example 2 3—oxidation 7, 8-dihydro-6, 6-dimethyl 7-Hydroxy-8 8- (1-hexazine π than fluorenyl) -6H-Nanone [2,3-f] benzo-2,1,3__diazole (Please read the notes on the back before filling (This page)

Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Cooperative Society, and printed at room temperature while stirring 9 2 4mg (2.88 mmol), 3, 4-dihydro-2, 2-dimethyl-1, 3-hydroxy_4 (1 Hexagene B is steeper than 6-amino_7_nitro-2H-phenylhydrazone [b] piperan, 0.7mj? 50% potassium hydroxide, 4mj ^ dichloromethane, 1 Omg

Bu4N + Br—, while adding 4.97 g (4.03 mmol) of 6% Na a C aqueous solvent, the reaction was carried out for 9 hours. After the organic layer is separated, the paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3. 10,000 40-A7 _B7 ___ V. Description of the invention (38) Extract the secondary aqueous layer with dichloromethane, and The dichloromethane was laminated together, washed with water and dried over anhydrous sodium sulfate. The residue after distilling off the solvent was treated by silica gel column chromatography (solvent, ethyl acetate: hexane = 1: 3 (v / v) to obtain 297 mg (yield: 43%) of the labeled compound. A part of it is dissolved in ethanol, HCj? -Et 0H solution is added, and anhydrous ethanol is added to obtain the hydrazone of the labeled compound with yellow crystals.

Melting point: 2 1 0 ~ 2 1 3 ° C Synthesis Example 3 7,8 —dihydro_6,6 —dimethyl — 7 —hydroxyl 8 — (1 —hexahydropyridyl) — 6H_piperano [2,3 — f] Benzene-1,2,3, -P-dioxazol ^^^ 1 · ^^^^ 1 nm ^^^^ 1 ^^ — ^ 1 vm —1 A 1— Bnn nn — m ping.,-> * · '.,}. / -----, · (Please read the notes on the back before filling this page)

Employees of the Central Bureau of Standards of the Ministry of Economic Affairs, a cooperative, printed 3, 2-7 7mg (0.93 millimolar) of the synthesis example at a temperature of 140 ° C. 3-Oxidation 7, 8-Dihydro-6, 6-2 Methyl-7-hydroxy-8- (1-hexahydropyridyl) -6H-erfuro [2,3-f] phenylhydrazine-2,1,3-P-diazole, 6mi ^ ethylene glycol, 60 mg (0.93 millimolar NaN2, react for 1.2 hours. After cooling, pour the reaction solution into chloroform and extract three times. Laminate chloroform together. Applicable to China Paper Standard (CNS) A4 (210X297) 83. 3. 10,000 -41-A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (39) The solvent was distilled off after drying with sodium sulfate. Column chromatography (solvent, ethyl acetate) : Hexane = 1: 3 (v / v) The residue was treated to obtain 8 4 mg (yield 30%) of the labeled compound as an oil. A part of it was dissolved in ethanol-ether and HC f-E t OH was added. A pale yellow crystal of the compound of the above described acetic acid can be obtained. Melting point: 2 0 2 ~ 2 0. 5 ° C Synthesis Example 4 7, 8-Dihydro-δ, 6-Dimethyl-7-Hydroxy-8- (1 — Pyrrolidinyl) -6Η-piperano [2,3-f] phenylhydrazone-2,1,3-dioxadiazole 0 丄: if fX Me —reflux while stirring for 3 hours 1 5 Omg (0. 6 8 7 millimoles) 3_oxidized 7,8-dihydro-6,6-dimethyl-1 7,8.-epoxy-6H-Nanone [2 '3-f] benzene fluorene-2 , 1,3-P-diazole, 63 " pyrene (0.756 mmol), pyrrolidine, 2mj? Ethanol. The solvent was distilled off to fractionate by thin layer chromatography (solvent, acetic acid). Ethyl acetate: hexane = 1: 1 (v / v) The residue was treated with 0 to obtain 120 mg (yield 60%) of the labeled compound. A part of it was dissolved

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3. 10,000 (Please read the notes on the back before filling this page) •--!! 1 V. _ --1T --- -1--0 ^ --------------- 42 A7 B7 V. Description of the invention (40) In dry ether, add H.C and Et 0H to get shallow. The yellow crystalline labeled compound osmium acid. Melting point: 2 0 8 to 2 9 ° C. Synthesis Example 5 7,8—Digas-6,6-Dimethyl-7- Xiangyi-1.8 Monomethylamino-6H—Nanino [2,3-f] phenylhydrazone-2,1,3— Moxadiazoles ―-- J 1-- (Please read the back and front precautions before filling out this page)

Printed using a pressure-resistant tube at the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, and stirred at 60 ° C for 3 days 30 Omg (1.337 mmol) 7,8-dihydro-6,6-dimethyl-7 , 8-epoxy-6H-piperano [2,3-f] phenylhydrazone-2,1,3-pyridadiazole, 0.53 g of 40% methylamine, 15 m of ethanol. After the reaction, the solvent was distilled off, and the residue was treated by thin-layer chromatography (solvent solvent, ethyl acetate: methanol = 1 0: 1). 263 mg (yield 77%) of the title compound was obtained. Dissolve a part of it in dry ether and add H C β — E t Ο Η to obtain the labeled compound acetic acid 塩 0 with colorless crystals. Melting point: 244.5 5 ~ 260 ° C. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3. 10 000 -43-, A7 B7 V. Description of the invention (41) Synthesis example 6 7, _ 8 — Dihydro-6, 6 —Dimethyl—7—Ethyl— 8— (4-fluorobenzyl) amino—6H —Urano [2,3-f] phenylhydrazine-2 :: L, 3—Dioxazole

-Reflux while stirring for 20 hours 15 mg (0.68 7 mmol) 7,8-dihydro-6,6-dimethyl-7,8_epoxy-6H-pirano [2,3 — f_] Benzene_2,1,3 — Shuji Mile, 8 6 # 5 (0.7 7 6 mmol) 4 Monofluorobenzylamine, 2 Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed (Please read the notes on the back before filling out this page) mi ethanol. After the solvent was distilled off, the residue was treated with thin layer chromatography (solvent, ethyl acetate: hexane = 1: 2) to obtain 204 mg (yield: 8 6%) of the labeled compound. Dissolve a part of it in dry ether and add H C $ _ E t Ο Η to obtain the labeled compound 塩 acid 塩 which is colorless crystal. Melting point: 2 0 7 to 2 1 0 ° C. Synthesis Example 7 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3.10,000 -44-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A 7 B7 5. Invention Description (42) 7, 8-dihydro-6,6-dimethyl-7-hydroxy-8-benzylamino-6H-pirano [2,3-f] phenylhydrazone-2,1,3-fluorene

Using benzylamine, the same procedure as in Synthesis Example 6 was used to synthesize the labeled compound. 0 NMR (6 OMHz, CDCi23, dppm): 7. 7 7 (1 Η), 7.3 7-6.9 2 (5 Η), 6.81 (1 Η) ), 3. 9-3. 8 (4 Η), 2. 7 3 (2 ，), 1.5 1 (3 Η), 1. 2 5 (3 Η). Synthesis Example 8 7, 8— Digas One 6,6 —Dimethyl-1.7 —Ethyl-8_ (N_ This paper size applies the Chinese National Standard (CNS ') A4 specification (210X297 mm). 83.3.10,000 I ---, ----- -^ ---------? 1 ------ (Please read the notes on the back before filling out this page) B7 V. Description of the invention (43) Phenyl-N-methyl) amine 6H-piperano [2,3-f phenylhydrazone-2,1,3-dioxadiazole

(Please read the precautions on the reverse side before filling out this page) Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Cooperative Consumers' Cooperatives. Use N-methylaniline as described in Synthesis Example 6 to synthesize the labeled compounds. The osmic acid of the labeled compound has a melting point of 148 ~ 150 ° C. Synthesis Example 9 7, 8-Dihydro-6, 6-Dimethyl-7-Hydroxy-8-Cyclohexylamino-6H-thiopyrano [2,3-f] phenylhydrazone-2,1,3—shu Diazole

83. 3. 10,000 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) -46-A7 B7 V. Description of the invention (44) Cyclohexylamine and Synthesis Example 6 are used to obtain the mark Compound. The labeled compound is osmic acid, melting point: 208 ~ 2 0 ° C. Synthesis Example 1 0 7,8 —dihydro-6,6-dimethyl — 7 —hydroxyl 8 — (4-methyl-1 hexahydropyridyl) — 6H —piperano [2,3 — f] Benzene 1,2,3 — _ diazole (read the notes on the back of the book first, then fill out this page)

Me I N

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Using N-methylhexahydropyridine trap as in Synthesis Example 6 to obtain the labeled compound (75%) as yellow crystals. Melting point: 225 ~ 226 ° C. MS: 70 (100%), 246 (56%), 3 1 8 (M +, 13%). Synthesis Example 1 1-7,8 —Digas_6,6 —dimethyl-7 —Cyclo_8 — (1 —Hexahydropyridyl) —6Η —Pirano [2,3 — ί] Benzene —2, 1, 3 —Ebodiazole This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) 83. 3. 10,000 -47-A7 B7 V. Description of the invention (45) Η

A hexahydropyridine trap was used as in Synthesis Example 6 to obtain the title compound (72%) as pale yellow crystals. Melting point: 2 4 5 to 2 4 6 ° C. MS: 56 (67%), 232 (100%), 304 (M +, 8%). Synthesis Example 1 2 7,8-dihydro-6,6-dimethyl-1-7-hydroxy-8- (4-phenyl-1-hexahydropyridyl) -6H-pirano [2,3 — f] Benzene-1,1,2,3-Sudadiazole (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

83. 3. 10,000 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -48 _ A 7 B7 V. Description of the invention (46) Use N-phenylhexahydropyridine trap, and Synthesis Example 6 — The labeled compound was obtained by the same operation (75%). MS: 132 (100%), 308 (36%), 380 (M +, 32%). The title compound was obtained as colorless crystals. Melting point: 198 ~ 2 0 1 ° C. Synthetic Example 1 3,7,8—Digas-6,6-Dimethyl-7-Meridyl-8— (4-Phenyl-1—N—Hexafluoropyridyl) —6H-Nanone [2 ， 3 — f] Benzamidine-2,1,3-Dioxadiazole (Please read the precautions on the back before filling this page)

Ph

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Using 4-phenylhexahydropyridine, the same as in Synthesis Example 6 was used to obtain the labeled compound (87%). MS: 186 (21%), 30 7 (100%), 3 7 9 (M +, 4%). The title compound is obtained from colorless crystals. The paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) 83.3. 10,000 -49-Printed by A7 B7, a staff member of the Central Standards Bureau of the Ministry of Economic Affairs. 47) Melting point: 195 to 197 ° C. Synthesis Example 1 4 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2,3,4-tetrahydroisoquinoline-2-yl) -6H-pirano [2,3-f] Benzylhydrazone-2,1,3-dioxadiazole

Using 1,2,3,4-tetrahydroisoquinoline, the same operation as in Synthesis Example 6 was carried out to obtain the labeled compound (80%). MS: 26 2 (32%), 279 (100%), 35 1 (M +, 4%). . The title compound was obtained from colorless crystals. Melting point: 1 88.5 to 190 ° C. Synthesis Example 1 5 7, 8-Di-M-6,6-Dimethyl-7-Cyclo-8- (4.- Morpholinyl) -6 fluorene-piperano [2,3-f] benzene幷 2,1 This paper size is applicable to China National Standard (CNS) A4 specification (2 丨 0X297 mm) .. 833.1 10,000 ---------------- 21 .-- -.—— Order ------ (Please read the notes on the back before filling out this page) -50-A7 B7 V. Description of the invention (48), 3-oxadiazole 0

(Please read the precautions on the reverse side before filling out this page) & Use morpholine in the same manner as in Synthesis Example 6 to obtain the labeled compound (11%). Melting point: 185 to 186.5 ° C. Synthesis Example 1 β 7,8—Digas-6,6—Dimethyl.yl-7—Cyclo-8— (3-methoxypropylamino) -6H-pirano [2,3-f] benzene幷 1-2,1,3-D oxadiazole Central Laboratories of the Ministry of Economic Affairs of the Ministry of Economic Affairs t Cooperatives printed H, N / (CH2) 3OMe

83.3. 10,000 This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (49) Using 3-methoxypropylamine as in Synthesis Example 6—the labeled compound (6 0 %). M S: 1 7 7 (100%), 2 3 5 (100%), 289 (M + -18, 1%). Melting point: 175.5 to 178 ° C. Synthesis Example 1 7 7,8-dihydro-6,6-dimethyl-1-7-hydroxy-8- (3-ethoxycarbonylamino)-6H-urfuro [2,3-f] phenylhydrazone-1 2,1,3-Esotriazole (please read the precautions on the back before filling this page) H, N > (CH2) 3C02Et

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Using 4-monoaminobutyric acid, the same as in Synthesis Example 6 was used to label the life (38%). The title compound was obtained as colorless crystals. Melting point: 1 89 ~ 191 ° C. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3. 10,000 -52-A7 B7 V. Description of the invention (50) Synthesis example 1 8 7, 8—Dihydro-6, 6—2 Methyl-7-hydroxy-8-ethoxycarbonylamino-6H-erfuro [2,3-f] phenylhydrazine-2,1,3 diazadiazole H, N / CH2C02Et

(Please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Using ethyl glycine, the same as in Synthesis Example 6 was used to obtain the labeled compound (5%). The title compound was obtained as an orange oil. Synthesis Example 1 9 7, 8-Digas-6, 6-dimethyl_7 —Cyclo-8_ (3-chloropropylamino) -6H-piperano [2,3 — ί] phenylhydrazine_2, 1 ， 3 _ Sudadiazole This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83. 3. 10,000 53 V. Description of invention (51) A7 B7 (^^ 2) 3 ci

Using 3-chloropropylamine, the title compound (20%) was obtained in the same manner as in Synthesis Example i. The title compound was obtained as colorless crystals. Melting point: 2 16 to 220 ° C. Synthesis Example 2 0 7, 8-Digas-6, 6-Dimethyl-7-Mesityl 8-(2 -Hydroxyethylamino)-6H-Piperano [2,3-f] phenylhydrazone- 2,1,3 _Padiazol (Please read the notes on the back before filling out this page) The Central Bureau of Standards of the Ministry of Economic Affairs has printed 2 copies of the breast

Using ethanolamine, the title compound (89%) was obtained in the same manner as in Synthesis Example 6. The title compound is obtained by colorless crystals. The paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm). 83. 3. 10,000 -54-Printed by A7 B7, Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Description of the invention (52) Melting point: 200 ~ 240 ° C. Synthesis Example 2 1 7,8-diaza-6,6-dimethyl-7-xiangyl-8-amino-6H-uran [2,3-f] phenylhydrazone-2,1,3- _Diazole

Dissolve 0.82 (3.8 millimolar) 7,8-dihydro-6,6-dimethyl-1,8-epoxy- 6H-piperano [2,3-f] phenylhydrazine-1 1,2,3,3-dioxadazole was reacted at 25mj ^ l 6.7% NH3-Et OH in a pressure tube at 60 ° C for 4 8 hours. After the solvent was distilled off from the reaction solution, a silica gel layer was used. Analysis (dissolving solvent, ethyl acetate: methanol = 5: 1, treating the residue to obtain 0.77 g (yield: 8 7%) of the title compound as a brown solid, dissolving a part of it in ethanol, and recrystallizing to obtain Pure colorless crystalline labeled compound. Melting point: 2 2 3 ～ 2 25 ° C. NMR (CDCla + DMSO-d6) i (ppm): 1.2 6 (3 Η), 1.4 9 (3 Η), This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 83.3. 10,000 I ---: ----- J ------, w ------ air r ... / IV, 1 .. (Please read the notes on the back before filling this page) 55 A7 B7 V. Description of the invention (53) 2.80-3.30 (5H) »3. 3 3 (1 Η), 3.78 (1 Η) , 6.8 2 (1Η), 7.98 (1Η), MS: 133 (50%), 163 (100%), 2 3 5 (M +, 3%). Synthesis Example 2 2 7 , 8 —dihydro (one 6 , 6-Dimethyl-7-meryl-8-methyladenoyl-6H-piperano [2,3-f] phenylhydrazine-2,1,3-pyridadiazole (Please read the precautions on the back first (Fill in this page again) ¥

, 1T

〇 II Hs ^ CNHMe N

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, 200mg (0.850 mmol) at room temperature, 7,8-diaza-6,6_dimethyl-1 7-base-8-amine-6 Η — Piperano [2,3-f] phenylhydrazine-2,1,3_esodiazol 2 m and dichloromethane, 5 5 " and (0 _ 9 3 5 mmol) ) Methyl isocyanate, stirred for 23 hours, and the precipitated crystals were filtered to obtain 2.7 mg (yield: 92%) of the title compound. This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 83.3.10,000 -56-Β7 V. Description of the invention (54)

Melting point: 2 1 3 ~ 2 1 5 ° C MS: 44 '202 (3% 2 7 4 (M-Ha〇, 6%). Synthesis example 2 3 7, 8-dihydro-6, 6-dimethylamine -6H-piperano [2,3 ~ f diazole-7-hydroxy-8-methylthiourea] phenylhydrazine-2,1,3 -fluorene

(Please read the precautions on the back before filling out this page.) Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 200mg (ο · 850mmol) at room temperature 7,8 dihydro-6,6 — Dimethyl-7 ~ hydroxy-8 monoamino-6H- piperano [2,3-f] phenylhydrazine-2,1,3 — Π 2 mile 2 0 methylene chloride, add 6 to this solution 8 mg (0. 935 mmol) of methyl isothiocyanate was stirred for 2 3 hours, and the precipitated crystals were filtered to obtain 122 mg (yield: 4 7%) of the title compound as colorless crystals. Melting point: 2 1 3 to 2 1 5 ° C. M S: 91 (62%), 202 (67%) »290, 308 (M +, 27%). This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83. 3.10,000 -57-A7 B7 V. Description of the invention (55) Synthesis example 2 4 7, 8-dihydro-6, 6 —Dimethyl-1 7 —hydroxyl 8 —phenylureido-6H —piperano [2,3-f] phenylhydrazine-2,1,3 —fluorenediazole

H. .CNHPh N

(Please read the precautions on the back before filling in this page) Stir 20 Omg (0.850 mmol) at room temperature 7, 8-digas-6, 6-dimethyl-7-Xiangji_ 8-Amino-6H —piperano [2,3 — f] phenylhydrazine_2,1,3 — Df diazole 20 m 芡 methylene chloride, and 102 / ^ $ (0.935 Millimolar) phenyl isocyanate was stirred for 4 hours, and the precipitated crystals were filtered to obtain 203 mg (yield: 6 7%) of the title compound as colorless crystals. Printed by the staff of the Central Bureau of Standards of the Ministry of Economic Affairs. Co., Ltd. Melting point: 2 1 5 ~ 2 17 ° C MS: 9 3,163 (56%), 321 (20%), 3 5 4 (M +, 10%). Synthesis Example 2 5 7,8—Dihydro-6,6—dimethyl_7 —Hydroxy_8 —Trichloroethane 83. 3. 10,000 The paper size is applicable to China National Standard (CNS) A4 (210X297 mm) -58-A 7 B7 V. Description of the invention (56) Glucosino-6H-piperano [2,3-f] phenylhydrazine-2,1,3-pyridadiazole

(Please read the notice on the back of the first cabinet and fill in this purchase) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, stirring at room temperature 20 Omg (0.850 mmol) 7, 8-two gas one 6 , 6-Dimethyl-1.7-Ethyl-8-amino-6H-piperano [2,3-f] phenylhydrazine-2,1,3-diazole 2 m In this solution, 100 y (0.935 mmol) of trichloroethyl isocyanate was added to this solution, stirred for 5 hours, and the precipitated crystals were filtered to obtain 9 Omg (yield 2 5% ) Labeled compound as colorless crystals. Melting point: 2 4 8 ~ 2 5 0 ° C. MS: 44, 163 (43%), -4 2 2 (M +, 2%). Synthesis Example 2 6 7 ， 8-Digas (-6, 6-dimethyl-7-meryl (3-chloropropylureido) -6Η-piperano [2,3 — ί] benzene 幷 _2,1 , 3 — Sudadiazole This paper is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) 83.3. 10,000 -59-V. Description of the invention (57) A7 B7 〇 HkN, CNH (CH2) 3a

Employees of the Central Bureau of Standards of the Ministry of Economic Affairs, Co-operative Society printed 400 mg (1.70 mmol) at room temperature and stirred 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amine Benzyl-6-pyrido [2,3-f] phenylhydrazone-2,1,3-pyridadiazole 40 m 芡 dichloromethane. To this solution was added 192 (1.8 8 mmol). (Ear) 3-chloropropyl isocyanate, stirred for 5 hours, and filtered the precipitated crystals to obtain 25 mg (yield: 41%) of the title compound as pale yellow crystals. Melting point: 8 3 ~ 8 5 ° C. M S: 41 (53%), 163, 318 (93%), 354 (M +, 5%). Synthesis Example 2 7 .7,8 — — M 6-6, 6 — monomethyl — 7 — mesityl 8 — (2 — chloroethylureido) — 6Η — piperano [2, 3_f] benzene # 2 1,2,3-U-diazole C, please read the notes on the back before filling in this page) Order a line '' This paper size applies to China National Standard (CNS) A4 size (210X297 mm) 83. 3. 10,000 -60 -A7 B7 V. Description of the invention (58) 〇H, n ″ NH (CH2) 2C1

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, stirring at room temperature 40 Omg (1.70 millimolar) 7,8 —dihydro-6,6 —dimethyl-1 7 —hydroxyl 8 —amino 6H-piperano [2,3-f] phenylhydrazone-2,1,3-fluorenediazole, 40 m; methylene chloride, add 2 0 0 # $ (1 · 8 7 Mol) 2-chloroethyl isocyanate, and stirred for 6 hours. The precipitated crystals were filtered, and # 4 8 Omg (yield: 83%) was obtained as the title compound as colorless crystals. Melting point: 1 7 8 to 18 0 ° C. MS: 87 (57%), 163, 304 (78%), 3 4 0 (M +, 8%). Synthesis Example 2 8 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-isopropylureido-6fluorene-piperano [2,3-f] phenylhydrazone-2,1,3 -0 bisdiazole (please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3. 10,000 61 V. Description of the invention (59) A7 B7 0

H CNH-i-Pr N

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, stirring at room temperature 20 Omg (0 · 8 50 mmol.) 7, .8 —dihydro-6, 6 — dimethyl — 7 — hydroxyl — 8 — Amine 6Η —piperano [2,3 — f] benzene 幷 —2,1,3 ′ — _-diazole, 20 m 芡 methylene chloride, 9 2 / / $ (0. 9 3 5 mmol) isopropyl isocyanate and stir for 6 hours. The precipitated crystals were filtered to obtain 12 mg (yield: 44%) of the title compound as colorless crystals. Melting point: 2 0 1 to 2 3 ° C. MS: 43 (40%), 202, 302 (20%), 3 2 0 (M +, 12%). Synthesis Example 2 9 7,8-dihydro-6,6-dimethyl-1-7-hydroxy-8-ethoxycarbonylamino-6H-erfuro [2,3-f] phenylhydrazone-2,1, 3 — oxadiazole (please read the precautions on the back before filling this page), · ιτ 线 Ε · This paper size is applicable to China National Standard (CNS) 8 4 specifications (210 × 297 mm) 83. 3. 10,000 -62- A7 B7 Printed by the staff of the Central Bureau of Standards of the Ministry of Economic Affairs t Cooperatives V. Invention Description (6d) 0 ττ Ί H COEt

Stir 20 Omg (0.850 mmol) at room temperature 7, 0.8 dihydro-6, 6-dimethyl-7-hydroxy-8-amino-6H-pirano [2, 3-f] phenylhydrazine_2,1,3-diazole, 1 6 6 # (1.19 mmol) triethylamine, 20 mg dichloromethane. To this solution was added 1 1 4 '(1.19 mmol) of ethyl chloroformate and stirred for 21 hours. The reaction solution was washed three times with water and then dried over anhydrous sodium sulfate. The residue after distilling off the solvent was subjected to silica gel column chromatography (solvent ethyl acetate: methanol = 20: 1 (v / v)) to obtain 2.7 mg (yield: 8 7%) of the title compound as a yellow oil. . MS: 133 (48%), 235, 307 (M, 25%). Synthesis Example 3 0 7, 8-Dihydro-6, 6-dimethyl-7-hydroxy-8-(2-chloroethoxycarbonylamino)-6H-piperano [2,3-f] phenylhydrazone _2,1,3 -Dioxadiazole This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) 83.3. 10,000 -63-. —. ^} Thread: "+ -J / V ( Please read the notes on the back before filling this page) A7 B7. · _ 丨 丨 V. Description of the invention (6l) 0 Hn ^ CO (CH2) 2C1

Stir at 40〇111§ (1.7 0 mmol) at room temperature 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pirano [2,3-f Benzene hydrazone-2,1,3-P oxadiazole, 2 6 0 " fluorene (1.887 mmol) triethylamine, 400 mg of dichloromethane. To this solution was added 193 a $ (1.87 mmol) 2-ethyl formic acid and stirred for 2 hours. The reaction solution was washed three times with water and then dried over anhydrous sodium sulfate. The residue after distilling off the solvent was recrystallized with chloroform to obtain 507 mg (yield: 8 7%) of the title compound as pale yellow crystals. Melting point: 1 6 4 to 16 6 ° C. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) MS: 133 (48%), 235, 307 (M +, 25%). Synthesis Example 3 1 7, 8-Digas-6,6-Dimethyl-7-Cyclo-8- (2_oxy-P-oxazolin-1-yl) -6H-piperano [2,3 -f] Benzene 幷 —2,1,3- 曜 2 mile The paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) 83. 3.10,000 -64-V. Description of the invention (62) A7 B7

C 乂. Printed by the Consumer Cooperatives of the Central and Southwestern Provincial Bureau of the Ministry of Economic Affairs of the People's Republic of China Printed in a nitrogen atmosphere and heated under reflux at room temperature for 26 hours and 40 Omg (1.17 mmol) of the compound obtained in Synthesis Example 30, 3.2 g (23.4 mmol) potassium carbonate, 3.8 mg (2.34 mmol) potassium iodide, 5 Ome anhydrous acetone. After returning to room temperature, insoluble matters were filtered, ethyl acetate was added to the filtrate, and the solution was washed three times with water. The residue was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was treated with silica gel column chromatography (solvent, ethyl acetate: methanol = 10: 1 (v / v)) to obtain 339 mg (yield 94%) of a brown oil The title compound. A part of this was recrystallized with ethyl acetate to obtain yellow crystals (melting point: 17.7. 5 to 18 0C). MS: 43 (25%), 272, 287 (65%), 305 (M +, 8%). Synthesis Example 3 2 7 '8——Gas-6,6-dimethyl-7-Cyclo-8- (2-oxy-3-imidazoline-1-yl) -6H-pirano [2- 65-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 83. 3. 10,000 (Please read the notes on the back before filling this page) V. Description of invention (63) A7 B7 f Benzenepyrene-2,1,3-pyridadiazole

Using the compound obtained in Synthesis Example 27 and the same operation as in Synthesis Example 31, the labeled compound (34%) was obtained as colorless crystals. Melting point: 2 5 1 ～ 2 5 2. 5 ° C. Synthesis Example 3 3 7, 8-Dihydro-6-yl-6 哌 _piperanodimethyl-7-hydroxy-8-cyclohexyl urea 3-f] phenylhydrazone-2,1,3 — Β Bi (Please read the notes on the back before filling out this page)

Using the cyclohexyl isocyanate, the same operation as in Synthesis Example 2 2 was carried out to obtain the labeled compound (28%) as colorless crystals. Melting point: 2 0 3 to 2 6 ° C. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3. 10,000 -66-A7 B7 master and invention description printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (64) Synthesis Example 3 4 7, 8-dihydro-6,6-dimethyl-1 7-hydroxy-8- (butyryl) -6H-piperano [2,3_f] phenylhydrazone-2,1 3-fluorenediazole

H, xCNH-t-Bu N

Using the third butyl isocyanate, the same operation as in Synthesis Example 2 2 was performed to obtain the title compound (52%) as colorless crystals. Melting point: 2 0 3 to 2 5 ° C. Synthesis Example 3 5 7, 8 —Digas-6, Amine_ 6 Η —Pyranoxadiazole_dimethyl_ 7 —Hydroxy-8—methoxycarbonyl 2,3-f] phenylhydrazone_2, 1, 3 —

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 83. 3. 10,000 (Please read the notes on the back before filling out this page) -67-A7 B7 V. Description of Invention (65) Use Methyl chloroformate was operated in the same manner as in Synthesis Example 29 to obtain the labeled compound (19%) as a yellow oil. Synthesis Example 3 6 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (third butylthioadenos) -6H-piperano [2,3_f] phenylhydrazone-2,1 , 3-Dioxadiazole (Please read the precautions on the back before filling out this page)

Hs M ^ CNH-t-Bu N

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Using tert-butyl isothiocyanate, the same operation as in Synthesis Example 23 was carried out to obtain the labeled compound (57%). Synthesis Example 3 7 7,8-dihydro-6,6-dimethyl-1-7-hydroxy-8- (2-oxyhexahydropyrimidine-1 1-yl) -6H-piperano [2,3- f] Phenylhydrazone—2,1,3—_diazole This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 83. 3. 10,000 -68-V. Description of the invention (66) A7 B7

The compound obtained in Synthesis Example 26 was used in the same manner as in Synthesis Example 31 to obtain the labeled compound (39%) as colorless crystals. Melting point: 2 3 3 to 2 3 4 ° C. Synthesis Example 3 8 7,8-dihydro-6,6-dimethyl-1 7-hydroxy-8- (3-chloropropoxycarbonylamino) -6H_piperano [2,3-f] phenylhydrazone 1,2,1,3 — U 咢 Diazole 0.h, n_A) (ch2) 3ci (Please read the notes on the back before filling out this page) Alignment line 'Printed by the Central Bureau of Standards, Ministry of Economic Affairs

Using 3-chloropropyl chloroformate, the same operation as in Synthesis Example 30 was performed to obtain the labeled compound (100%) as a yellow oil. Synthesis Example 3 9 This paper size is in accordance with Chinese National Standards (CNS) 8-4 specifications (210 X 297 mm) 83. 3. 10,000 -69-A7 B7 V. Description of the invention (67) (Please read the notes on the back before (Fill in this page) 7, 8-dihydro-6, 6-dimethyl-7-hydroxy-8- (2-oxytetrakis (Hydroxy-3-yl) -6H-Nanone [2, 3 — f] Benzamidine—2,1,3-—diazole

Using the compound obtained in Synthesis Example 38, the same operation as in Synthesis Example 31 was performed to obtain the labeled compound (34%). Melting point: 220 to 223 ° C. Synthesis Example 4 0 3 —Oxygen 7,8-dihydro-6,6-dimethyl-1-7-ethoxyl-8-diethylamino-6H—pirano [2,3-f] benzene幷 1-2,1,3-D Printed by the Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

X ^^ OCOUc JL-Me Me 83.3. 10,000 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -70-A7 A7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs B7 V. Invention Description (68 ) To 103 mg (0.34 mmol) of the compound obtained in Synthesis Example 1 was added lmj? Pyridine, 130 mg (1.27 mmol) of acetic anhydride, and the mixture was stirred at 80 ~ 90 ° C for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was treated with silica gel column chromatography (solvent ethyl acetate .: n-hexane = 1: 3 (v / v) Rf = 0.3) to obtain 90.4. mg (yield 7 7%) of the title compound as a yellow solid. Synthesis Example 4 1 7,8-dihydro-6,6-dimethyl-1,7-hydroxy-1,8-diethylamino-6H-piperano [2,3 — ί] phenylhydrazine-2,1,3 —Panadiazole '

Dissolve 3 1 0 m (1.01 mmol) of the compound obtained in Synthesis Example 1 in 3 g of benzene, add 0.20 g (1.2 mmol) of triethyl phosphite, and heat at 60 ° C for 1 After an hour, it returned to room temperature and stirred overnight. The solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography (solvent ethyl acetate: n-hexane = 1: 3 (v / v), Rf = 0.3) to obtain 267 mg (yield 9 1). %) The title compound as a yellow solid. Synthesis Example 4 2 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 male thin) 83. 3. 10,000 -71-----------------.--,- ------ Complete TV (Please read the notes on the back before filling this page) A7 B7 V. Description of the invention (69) 7,8-Dihydro-6,6-Dimethyl-7-acetamidine 8-diethylamino-6H-piperano [2,3-f] phenylhydrazone-2,1,3-dioxadiazole

(Please read the precautions on the back before filling out this page) The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed 220 mg (0.75 mol) of the compound obtained in Synthesis Example 41 with 2 m $ of pyridine, 0.29 g (2. 8 mmol) acetic anhydride, and stirred at 80 ~. 9 0 ° C for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography (solvent ethyl acetate: n-hexanedi 1: 3 (v / v) Rf = 0.3) to obtain 29.1 mg. (Yield: 8 3%) The title compound 0 as a pale yellow solid. Synthesis Example 4 3 7,8—mononitro-6,6—monomethyl-7—acetoxyoxy 8— (1-hexafluoro Dttn amidin) —6H —Nacura [2,3 — f] benzenepyrene-1,2,1,3 —Eunadiazole This paper is dimensioned to the Chinese National Standard (CNS) 8-4 (210X297 mm) 83. 3. 10,000 -72 A7 B7 V. Description of Invention (70)

OCOMe used the compound obtained in Synthesis Example 3 in the same manner as in Synthesis Example 4 2 to obtain the labeled compound (100%) as yellow crystals. Melting point: 1 5 8 ~ 16 0 ° C. Synthesis Example 4 4 7 5 8 —Dichloro-dimethyl — 7 —Cyclo-8 — (4 diethoxybutylamino) — 6 Η —piperano, 1, 3 — 咢 diazole-f 〕 Benzene I 2 (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

H.v. (CH2) 3CHC〇Et) 2 N

OH

83. 3. 10,000 This paper size is in accordance with Chinese National Standard (CNS.) A4 (210X297 mm) 73-Printed by A7 B7, Shellfish Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs --------____ V. Invention Explanation (71) 4-aminobutyl formaldehyde-acetal acetal was used in the same manner as in Synthesis Example 6 to obtain the labeled compound as a brown oil (9. Synthesis Example 4 5 7 '8 — —M_6' 6 —A —Xiangyi-8_ (2-Hydroxypyridine-1-yl) -6H-piperano [2,3_f] phenylhydrazone-2,1,3 — 0 bisdiazole

To 316 mg (0.832 millimoles) of the compound obtained in Synthesis Example 44 was added lmj? 2.5Ki osmic acid and 2mj? 1,4-dioxolane, and reacted at room temperature for 3 hours. An aqueous solution of sodium carbonate was added, and after hydration, it was extracted with diethyl ether. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography (solvent ethyl acetate: n-hexane = 1: 1 (v / v) Rf = 0.5) to obtain a yellow color. The title compound as an oil (40%). Synthesis Example 4 6 7, 8-Dihydro-6, 6-dimethyl-7-Methino 8-(3-Carbapropylamino) _6H_piperano [2,3_f] phenylhydrazone-2, 1 Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 83_ 3. 10,000 (Please read the notes on the back before filling this page) -a • Nickel-74-A7 __B7 V. Description of the invention (72), 3 —panadiazole

H.. (CH2) 3C02H N

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, 8 0.61118 (0.2 0 9 millimoles) was synthesized in Example 17. 17 of the compound obtained was added with 18.4 mg (0.460 millimoles), A solution of lm $ water and 4m ethanol was reacted at room temperature for 3 hours. 1 N osmic acid was added to make it acidic, and extracted with diethyl ether. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound as a colorless oily substance. Synthesis Example 4 7 7 '8 -Digas-6,6 -Dimethyl-7-Ethyloxy-8-amino-6H-piperano [2,3-f] phenylhydrazone-2,1, 3 —Esotriazole

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3.10,000 (Please read the notes on the back before filling this page) -75-A7 B7 V. Description of the invention (73) Dissolved 24 Omg (1.10 millimolar) 7,8-dihydro-6,6-dimethyl-1,7-epoxy-6H-piperano [2, 3-f] phenylhydrazone-2, 1,2,3-dioxadazole in 5τηβ dichloromethane. To this solution was added acetonitrile, 0.5 m) 2 BF3-diethyl ether mixture. After 30 minutes of reaction at room temperature, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was treated with silica gel column chromatography (solvent ethyl acetate: n-hexane = 1: 1 (v / v) R = 0.3) to obtain 152 mg of the labeled compound (yellow oil, yield 50%). MS: 163 (53%), 188 (100%), 2 7 7 (M +, 4%). Synthesis Example 4 8 7 '8-Digas-6,6-diethyl-7-Cyclo-8- (1-Hexahydropyridyl) -6 fluorene-piran.pyrano [2,3-f] benzene幷 —2,1,3—P-diazole (please read the precautions on the back before filling out this page) --5 Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 0

83. 3. 10,000 The size of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -76-, 8-piranopeptide mg (A7 B7 · *. V. Description of the invention (74) One side is mixed with 87. 7g (0.36 mmol) 7. Nitrogen ~ 6,6-diethyl-7,8-epoxy-6 ^ 1-2,3-f] phenylhydrazine-2,1,3-0f diazole , 6 Ί 0.72 mol) hexahydropyridine, 2m and ethanol, ~ reflux for 20 hours. After distilling off the solvent, the residue was treated by silica gel column chromatography (solvent. Ethyl acetate: n-hexane = 1: 1 (v / v) R = 0. 3) to obtain 30 mg of the labeled compound (yellow Oily substance, yield 2 5%} Synthesis Example 4 9 7,8—Digas-6,6-diethyl-7- Xiangyl-8 Group-6H—piperano [2,3_f] phenylhydrazone One 2,1-amine-m (Please read the precautions on the back before filling this page} Order

OH

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Online Economics. 7,8—Digas-1,6—6-Ethyl-7,8—Epoxy-6H—Pirano [2,3-f] phenylhydrazone-1 2,1,3-Dioxadiazole, the same as in Synthesis Example 2 1 to obtain the labeled compound (44%) as colorless crystals, melting point: 122 ~ 124 ° C. This paper standard is applicable to China National Standard (CNS) A4 specifications. (210 X 297 mm) 83.3. 10,000 -77-Α7 Β7 V. Hair & Sun and Moon Explanation (75) Synthesis Example 5 0 7, 8-Digas-1 6 Η-piperanozole-diethyl- 7-Hydroxy-8-methylureido 3-f] phenylhydrazone-2,1,3-fluorene

0 II H CNHMe N OH

Using the compound obtained in Synthesis Example 4 9 in the same manner as in Synthesis Example 2 2, the title compound (89%) was obtained as a brown oil. Synthesis Example 1 7,8—One gas one 6,6—diethyl 7—ethyl ethyloxy group 8—Amino-6H—piperano [2,3-f] phenylhydrazone-2,1,3— Esotriazole (Please read the notes on the back before filling out this page) Printed by the Central Consumers Bureau of the Ministry of Economy

〇CX) Me 83. 3. 10,000 This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) -78-A7 B7 V. Description of the invention (76) Use 7,8 —dihydro-6, 6 — Diethyl-7,8_epoxy-611-piperano [2,3 — 1] benzene hydrazone ~ 2,1 〇ηηο on 'Ο-卩 二 two miles, the same operation as in Synthesis Example 4 7- Obtain the pale yellow crystal of the compound (62%), melting point: 9 2 ~ 95 ° C. Synthesis Example 5 2 7,8—Dihydro-6,6-dimethyl-1 7-Hydroxycyano-3 —Third-butyl-1 —guanidino) -6 Η 3 — f] Benzene 1,2,1 , 3 — _diazole ~ 8 ~ (2 -piperano [2., (Please read the precautions on the back before filling out this page)

t-Bu order-line, printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, 9 mol), mol), triphenyl (9 mol), three heating and refluxing for 4 hours by 100 mg (0.2 as an example) 36 compound obtained, 97 mg (0. 37 phosphine, 4 0 // carbon tetrachloride, 4 Op meaning (0. 2 ethylamine, lmi? Dichloromethane solution), the solvent was distilled off under reduced pressure, and silica gel Column chromatography (solvent ethyl acetate: n-hexane = 1: 2 ίν / v) Ri = 0.1) Treatment. The residue was obtained as 77 mg of the title compound as pale yellow crystals. 122 mg (0.39) was stirred at room temperature. Millimoles) This compound is in accordance with Chinese National Standard (CNS) A4 specifications (210X297mm) 83.3.10,000 79 A7 B7 _ V. Description of the invention (77), 2 lmg (0.50 millimoles) atmosphere A solution of hydrazine, 2tnj? Tetragas furan, and 2 Omg diisopropylethylamine over 14 hours. The precipitated crystals were filtered to obtain 112 mg (yield 80%) of the title compound as pale yellow crystals. Melting point : 1 4 6 ~ 1 4 8 ° C. Synthesis Example 5 3 7,8 —Digas-6,6-dimethyl — 7. —hydroxyl g — (1 —hexahydropyridyl) —6H —piperan And [2, 3 — Bing] benzene-1, 2,3-triazole _ (Read Notes on the back and then fill the page)

Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 0.14g (0.44 mmol), 3,4-dihydro-2,2-dimethyl-2,3-hydroxy-1,4- (1-hexahydropyridyl ) 6-Amino-7-nitro-2H-phenylhydrazone [b] piperan in 23.7 g of ethanol, with 0.1 · 10 g of 5% palladium-carbon as the catalyst, with stirring, in the chamber It was hydrogenated at 1 atmosphere for 3 hours. The reaction solution was filtered by suction to remove the solvent, and the solvent was distilled off to obtain 0.12 g (yield: 95%) of 3,4 diazo-2,2 as a dark red oil. _Dimethyl-3_ Xiangyi-4 — (1-hexahydropyridine) -6,7-diamino-2H-phenylhydrazone [This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 male 83) 10,000 -80 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (78) b] Piran. This substance is unstable and is used next for diazotization. Dissolve all of the above diamine compounds in a mixture of 0.13 g of acetic acid and 0.23 g of water. Dissolve 3 5 mg (0.51 mmol) of sodium nitrite at room temperature at a time. . 15g water person. After confirming the fever, heat on a 8 Q ° C water bath for 1 minute. 20 m $ of water, 0.13 g of sodium oxide, and 4.0 g of sodium gaseous solution were added to the reaction mixture, and extracted with 40 mJ2 ethyl acetate three times. The ethyl acetate layers were laminated together and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off to obtain 0.10 g of a yellow-red powder, and 9 Omg thereof was refined by silica gel column chromatography (ethyl acetate-ethanol = 5: 1) to obtain 8 Omg (a cost-effective yield of the two projects). 7 2%) of the title compound as a light tan powder. MS: 2 8 4 (M + —H20, 18%), 230 (M + —72, 100%), 8 4 (5%). Synthesis Example 5 4 7, 8-Dihydro-6, 6-dimethyl-7-hydroxy-8-(1-pyrrolidinyl) -6 fluorene-piperano [2,3-f] phenylhydrazone-1 , 2, 3 — two miles

This paper size applies to China National Standard (CNS) A4 (2! 0X297 mm) 83. 3.10,000 (Please read the precautions on the back before filling this page),-° line -81-Central Standard of the Ministry of Economic Affairs Printed by the Consumer Cooperative of the Bureau A7 _____B7 V. Description of the invention (79) Dissolved 0.20 ^: (0. 6 5 mmol) 3, 4-dihydro-2, 2-dimethyl-2, 3-hydroxy-1 4 1 (1-pyrrolidinyl) -6-amino-7-nitro-2H-phenylhydrazine [b] piperan in 34.9 g of ethanol, and 0.15g of 5% palladium-carbon as the catalyst, stir It was hydrogenated at room temperature under 1 atmosphere for 3 hours. The reaction solution was filtered by suction to remove the solvent and the solvent was distilled off to obtain 3,4 of 17 Og (yield: 9 4%). —Gas-2,2—dimethyl—3—Shangi—4 .- (1-pyrrolidine) -6,7-diamino—211—phenylhydrazone [1]] piran 0 All of the above two The amine compound is dissolved in a mixture of 0.19 g of acetic acid and 0.34 g of water, and a person who dissolves 5 2 111 pressure (0.7 5 mmol) sodium nitrite in 0.2 2 water at one time at room temperature . After confirming the fever, heat in a water bath at 80 ° C for 3 minutes. The following are the same as those in Synthesis Example 5 3-Post-treatment, to obtain 16 Omg (the second project cost-effective yield 85%) of the title compound as a yellow-brown powder. MS: 288 (M +, 3%), 27 0 (M +-H2 0, 3%), 216 (M + —72, 88%), 188 (M + -100, 100%, 70 (22%). Synthesis Example 5 5 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3.10,000 ---- ^-I ^ —— I — one ------- order ---- --Line J // ....! .NM (Please read the precautions on the back before filling in this page) -82-A7 B7 V. Description of the invention (80) 7, 8 —Dihydro-6, 6 — 2 Methyl-7-hydroxy-8-diethylamino ~~ 6H-Nanone [2,3 — ί] Benzene-1,2,3-triazole

Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Co., Ltd., Co., Ltd. Dissolved 0.2〇8 (0.65 mmol) 3,4-Dihydro-2,2-Dimethyl-3-hydroxy-1 4-Diethylamino-6-6 Amine 7-nitro-2 hydrazone-phenylhydrazone [b] piperan in 3 4-9 g of ethanol, with 0.1 15 g of 5% palladium-carbon as the catalyst, with stirring, 'at room temperature, Hydrogenation was performed at 1 atmosphere for 2.5 hours. The reaction solution was filtered by suction to remove the solvent, and the solvent was distilled off to obtain 0.15 g (yield: 83%) of 3,4—two gas and one gas brown residue. 2,2-Dimethyl-1, 3-mer, 4-diethylamino-6,7-diamino-2, Η-phenylhydrazone [b] piran. All the above diamine compounds were dissolved in a mixed solution of 0.19 g of acetic acid and 0.34 g of water, and 5 2 mg (0.75 mmol) of sodium nitrite was dissolved at a time at room temperature. In 〇22g water. After confirming the fever, heat in a 80Ό water bath for 3 minutes. The following were all treated with Synthesis Example 5 3-sample post-treatment to obtain 7 Omg (the second project cost-effective yield of 3 7%) of the title compound as a light brown powder. I ---- ^ ---- ——N / T ------ Order ------ Line, "./V.. Ί. (Please read the notes on the back before filling this page ) This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 83. 3.10,000 -83-A7 B7___ V. Description of the invention (81) MS (FAB): 291 [(M + H) ”Synthesis example 5 6 7,8-dihydro-6,6-dimethyl-1 7-hydroxy-8- (1-hexahydro D than pyridyl) -6H-piperano [2,3-f] phenylhydrazone-2 , 1, 3 —sleep diazole

Employees of the Central Bureau of Standards, Ministry of Economic Affairs, printed by the cooperative, dissolved 0_28g (0.887 mmol), 3,4-dihydro-2'.2 —dimethyl-1 3 —Xiangji —4 — (1 —6 The MD ratio of acryl-6-amino-7-nitro-2H-phenylhydrazone [b] is ran in 44.8 g of ethanol, and 0.20 g of 5% palladium-carbon is used as a catalyst. Hydrogenated at room temperature and 1 atmosphere for 3 hours. The reaction solution was filtered by suction to remove the solvent, and the solvent was distilled off to obtain 0.24 g (yield: 95%) of 3,4—two gases—2, 2 of a dark red oil. —Dimethyl—3—Cyclo-4— (1-hexahydropyridine) —6,7—diamino—2H—phenylhydrazine [b] uran. To this was added 0.2 lg (0. 86 mmol) aniline, 4 g benzene, heated to reflux for 2.5 hours, and distilled off the solvent under reduced M, and then treated with silica gel chromatography (ethyl acetate-ethanol = 1: 3) to treat the remaining 83. 3.! 0, 〇〇〇 (Please read the precautions on the back before filling out this page) LINE 'This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm) -84-ΑΊ B7 5. Description of the invention ( 82) Slag to obtain 6 Omg (yield: 23%) Compound 0 MS: 84 (85%), 247 (100%), 3 1 9 (M *, 2%). Synthesis Example 5 7 7, 8-dihydro-6, 6-dimethyl-1 7-hydroxyl 8 — (1 —pyrrolidinyl) — 6 fluorene —piperano [2,3 — f] phenylhydrazine 2 —, 1,3 —bloxadiazole (please read the precautions on the back before filling this page)

Printed by the Consumer Standards Cooperative of the Central Standardization Bureau of the Ministry of Economic Affairs 3,4-dihydro-2,2-dimethyl-1 3-hydroxy-1 4 -6-amino group-7-nitro-2 fluorene-phenylbenzene [b ] Piran was operated in the same manner as in Synthesis Example 56 to obtain the title compound as a light brown oil (yield: 25%). Synthesis Example 5 8 7, 8_Digas-6,6-Dimethyl-7-Cyclo-8-diethylamino-6H-piperano [2,3-f] phenylhydrazone-2,1, 3 —The size of thiaben paper is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 83. 3. 10,000 85-A7 B7 V. Description of the invention (83) Diazole

Et ,, Et NJL ^ OH JL-Me Me uses 3,4-dihydro-2,2-dimethyl-1 3-hydroxy-1.4-diethylamino-6-amino-7-nitro-2 -Benzene hydrazine [b] piperan was operated in the same manner as in Synthesis Example 56 to obtain the title compound as a light brown oil (yield: 17%). Synthesis Example 5 9 (―) — 7,8—dihydro-6,6—dimethyl-7—hydroxy-8— (1-pyrrolidinyl) -6H—piperano [2,3_f] phenylhydrazone —2,1,3 —oxadiazole [Synthetic Example 4 Compound

(Please read the precautions on the back before filling out this page) 、 Reference example printed by r ^ v0HJL-Me \ 〇 ^ Mc at 15.0g (68.7 millimoles) for the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Of 1 compound

This paper size applies the Chinese National Standard (, CNS) A4 specification (210X297 mm.) 83. 3.10,000 —86-A7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs B7 V. Invention Description (84) 6 Om 芡 Ethanol To the solution was added 14.7 g (20.6 mmol) pyrrolidine, and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and 10 Om of water was added, followed by extraction with chloroform (100 Om 芡 XI, 3 Omj? X 2). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography (benzene: ethyl acetate = 5: 1-4: 1), and the resulting crystals were recrystallized from benzene-hexane (1: 2) to obtain 13.8 g (yield 6 9%). The title compound is a yellow crystal. To 13 g (44.9 millimoles) of the title compound, 2 4 0. mi? Ethanol solution was added 2 4 9 miH capric acid monomethanol (10%), and after stirring at room temperature for 3 hours, it was distilled off under reduced pressure. Solvent. Crystallization was performed with 2 5 Omj? 2-propanol to obtain 11.5 g (yield: 78%) of the title compound, osmium sulfonate, as colorless crystals. Melting point> 2 0 ° C (decomposed). Synthesis example. 6 0 (+) — 7,8 —diamino group 6,6 —dimethyl-7 —transyl group 8 — (1-pyrrolidinyl) -6H —piperano [2,3 — f] Benzylhydrazine_2,1,3-_diazole [Synthetic Example 4 compound optically active (+) body 0 — 1 m---1-- n i--1-^ II c ^ (Please first (Read the notes on the back and fill out this page)

This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 83. 3. 10,000 -87-printed by the staff of the Central Bureau of Standards of the Ministry of Economic Affairs and Cooperatives 1 0 g 2 6 0 g 6 0 0 g 3 5 0 g 1 0 0 g 1 5 0 g 3 0 g A 7 B7 V. Description of the invention (85) and Synthesis Example 5 9-The same operation was performed to obtain 15.0 g (yield 58%) of the title compound as yellow crystals. In the same manner, 12.9 g (yield: 82%) of the title compound, gadolinium sulfonate, was obtained as colorless crystals. Melting point> 2 0 0 ° C (decomposition) Preparation Example 1 Lozenge Synthesis Example Compound Lactose Microcrystalline Cellulose Corn Starch Hydroxypropyl Cellulose CMC-C a Magnesium Stearate 1.50 0 g The above ingredients are made into 10,000 tablets of sugar-coated spinach containing 1 mg of active ingredient in each tablet. Formulation Example 2 Capsules This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 83. 3. 10,000 (please read the precautions on the back before filling this page) Thread-88-A7 B7 V. Invention Explanation (86) Synthetic Example Compound Lactose Micro-Caking Cellulose Magnesium Stearate 10 g 4 4 0 g 1 〇 〇 0 g 5 〇 g Total amount 1,500 g After mixing the above ingredients in the usual way, add Gelatin gelatin, there are 0,000 capsules containing 1mg of active ingredient in each capsule (please read the precautions on the back before filling this page) Example 3 of the printed product printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Swelling agent compound 4 1 0 g 1 IPEG 4 0 0 4 7 9 s 1 Saturated fatty acid triglyceride line 1, 5 0 0 go -.- J-mint oil 1 S 1 1 (Polysorbate) 8 0 1 0 S 1 1 Full amount 2, 0 0 0 g According to the usual method, the above ingredients after mixing are filled into capsules of soft gelatin No. 3 to make 1 0,000 soft gelatin containing 1 mg of active ingredient per capsule. Agent. This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3.10,000 -89-V. Description of the invention (87) Preparation example 4 Ointment synthesis example compound 4 Flow paraffin cetyl alcohol white petrolatum hydroxybenzene Ethyl formate menthol A7 B7 2 0 6 8 gggggg (Please read the precautions on the back before filling out this page) 10 0. g Mix the above ingredients as usual to become a 1% ointment. The Central Bureau of Standards of the Ministry of Economic Affairs printed formulations for Industrial Cooperative Cooperatives. Example 5 Suppository Synthesis Example Compound 4 Witepsol H15 " Witepsol W35 '(polysorbate) 80 1 g 4 7 8 g 5 2 0 g 1 g Full amount 1, 0 0 0 g Glycerin Tri-ester compound brand name i Eps 〇 This paper is again applicable to China National Standard (CNS) A4 (210X297 mm) 83. 3. 10,000 -90-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5 Explanation of the invention (88) The above ingredients are melted and mixed according to the usual method, poured into a suppository container, and cooled and fixed into 1,000 suppositories containing 1 mg of active ingredient. Formulation Example 6 Λ Injection 4 mg Compound

Use 5 ml of distilled water for injection, after dissolving. [Pharmacological test example] Effect on myocardial contractility Test method: The heart is removed from a male Harlay strain mole, and the left atrium is separated in a Kreb Henseleit solution aerated with 95% oxygen / 5% carbon dioxide. In the organ bath filled with nutrients at 31 ° C and filled with nutrient solution, the specimen was suspended with a tension of 0.5 g. Myocardial contractility is via a bipolar platinum electrode, and electrical stimulation is applied through the wall [stimulation conditions: voltage is 2 times the threshold voltage of contraction available (V), stimulation time: 3 (m seconds), stimulation interval: 1 (Η z)] Record the contraction tension that occurred. After exchanging the nutrient solution for balance, cumulatively apply isoproterenol to the specimen to obtain the maximum contractile response. After washing the medicines, while exchanging the nutrient solution, balance for 60 minutes, and then observe the paper size with Chinese compounds using the Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3. 10,000 ------ ΓI-i—J -----— Order ------ line /! I. (Please read the notes on the back before filling this page) 91 A7 A7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 2. Description of the invention (89). The maximum response of isoproterenol was 1000% in advance, and the effect when each compound 100 and 300 was used was expressed as the percentage change. Results: The compounds related to the present invention showed a strong effect on increasing myocardial contractility as a function of concentration. [Table 7] Test results 1 Effect on myocardial contractility (Effective compound (Synthetic Example No. 0 Myocardial contractility change rate (% ') •) 1 0 0 # Μ 3 0 0 ^ Μ 1 2 4.7 5 2.7 2 4 4.2 8 4.0 4 5 5.7 13 5.0 3 6 6 7.5 Effect on the number of beats of the heartbeat The paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 〇297mm) 83. 3.10,000 (Please read the precautions on the back before (Fill in this page)

-92 A7 B7 V. Description of the invention (卯) Test method: (Please read the precautions on the back before filling out this page >> Remove the heart from the male Harlay strain mole and ventilate it with 95% oxygen / 5% carbon dioxide. The left atrium was separated from Kreb Henseleit solution. The specimen was suspended with 1 g of tension in an organ bath filled with nutrient solution at a temperature of 31 ° C. After exchanging the nutrient solution for balance, the isoproterenol was applied cumulatively. The maximum contractile response was obtained in the specimen. After washing the drug, the nutrition solution was exchanged, and the solution was equilibrated for 6 Q minutes, and then the effects were observed with each compound. The maximum response of isoproterenol was 100% in advance. The effect when using each compound 1 0 0 and 3 00 // M is expressed as the change rate%. Result: The compounds related to the present invention are related to the concentration and show a reduction in heart beat. 0 Printed by the Central Standards Bureau of the Ministry of Economic Affairs 83.3.! 〇, 〇〇 〇 This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) -93-A7 —_ B7 _ V. Description of the invention (91) [Table 8] Test results 2 pairs of pulses number Affecting effect Pulse rate change rate (%) Compound (Synthesis example N 〇.) ----- 100 a Μ 3 0 0 // Μ 1 -17. · 7 -73.3 2 — 1 2 • 8 — 25.0 4 — 15.6 —53-8 Test method for the effects of anesthetized dogs' heart function: * Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling in this education)

Male and female mixed dogs were anesthetized with pentostomate. Under artificial respiration, the blood pressure was inserted from the right thigh artery into the aorta of the abdomen, and the pressure transducer was used to measure it through a stress amplifier. The blood pressure waveform is used as a trigger, and the waveform is beaten by an instant heart pulse. Left ventricular pressure is measured by inserting a catheter pressure transducer into the left ventricle from the left carotid artery through a stress pressure amplifier. The instantaneous differential pressure of left ventricular pressure (the excitation velocity of right ventricular systolic pressure, LV dp / d 1, nax) is obtained by differentiating the left ventricular pressure with a differential component. The drug is dissolved in polyethylene glycol 400, ethanol, and water (mixing ratio 2: 3: 5). It can be put into the vein quickly through a cannula inserted in the left cutaneous vein, and the paper standard applies Chinese National Standard (CNS) A4. Specifications (210X297 mm) 83. 3. 10,000 -94-A7 B7 V. Description of the invention (92). Solvent alone confirms that it has no effect on cardiac function and blood pressure. Results: It was learned that the compounds related to the present invention have no effect on blood pressure, and have a strong effect of increasing cardiac contractility and reducing the number of heart beats. Test Result 3 The effect of intravenous administration of compound 5 9 (synthesis example number) (the compound (body) of compound 4) on anesthetized dogs on the rate of change (%) of the previous dose, the average of 3 cases (please Read the precautions on the back before filling in this page) Time (minutes) Order the amount of measurement items 5 10 20 (mg / kg) 0 1 3 Printed left ventricular pressure 1—Sub-differential 中 3 0 14 0 18 1-0 13.59.1 4 Pulse beats 1 3 -5 .8 -5.2 -4 0 -10.6 -11.0-10. Average blood pressure 1 3 .1 The size of this paper applies the Chinese National Standard (CNS) A4 specification ( 210X297 mm) 83. 3. 10,000 95-

Dazheng: .t1 ^ Supplement No. 83i〇2877 patent application supplementary explanation form (sincerity; ... |. | Daojia's Fencheng examples (> > all 塩 acid acid 塩) Synthesis example No. R1 R2 Melting point of properties ( C) 6 1 nPr nPr white powder 1 7 3 — 1 8 3 6 2 Η nPr yellow powder 2 4 8-2 5 0 6 3 Η-(CH2) 3〇Et yellow powder 1 7 5 _ 1 7 8 5 4 Εΐ nPr white powder 2 2 2-2 2 5 6 5 Et nBu yellow powder 1 8 〇-1 8 2 6 6 -ch2ch = ch2 -CH2CH = CH2 yellow powder 1 7 2-1 7 4 6 7 Η (ch2) 4oh Brown powder 2 2 0 — 2 2 3, 6 δ-(CH2) 2OH-(CH2) 2〇H Brown powder 1 0 S — 1 1 0 6 9 Me-(CH2) 2Ph White powder 1 9 0-1 9 3 7 0 Me JBu yellow powder 1 7 8-1 8 1 7 1 H -C (Me2) CH2Ph white powder 1 9 0-1 9 2 OH 7 2 Γ IS light yellow crystal 2 3 3-2 3 4 test result 1 pair Scenery of myocardial dysfunction_Effective compound (synthesis example No.) Myocardial contractile dysfunction rate (%) 100 μM 300 μM 1 24.7 52.7 2 44.2 84.0 4 55.7 135.0 8 88.5 103.8 12 116.7 150.0 15 22.0 61.0 21 Η.3 39.3 '23 71.4 90.5 32 9.0 31.0 34 50.0 90.9 36 67.5 3 7 13.0 77.0 45 17.5 19.2 53 1,5 5.8 59 51.9 148.5 60 22.5 39.8 61 140.0 140.0 62 72.7 118.2 63 28.6 78.1 64 100.0 109.5 65 90.9] 00,0 66 100.0 67 32.0 105.0 6S 18.0 47.0 69 76.0 85.0 70 150.0 150.0 71 83.0 100.0 72 6.7 20.0 Test Result 2 Compound (Synthesis Example No.)-2 4 12 15 21 23 32 34 37 45 52 53 59 60 Change rate of heart beat ⑽ 100 μΜ 300 μΜ -17 -12 -15 -19 -9 —9 -5 -17 -4 —11 -3 -65 -8 -20 -18 6 0 -73.3 -25.0 -53.8 -50.0 -34.0 -19.0 -21.1 -52.0 -6.0 -5.2 -28.2 -47.5 -40.0

.i.-

Supplement No. 83102877 Patent Application Table i plus Synthesis Example r1 is osmic acid) Synthesis Example No. R1 R2 Properties Melting point (t :) 6 1 nPr nPr White powder 1 7 3-18 3 6 2 Η nPr Yellow powder 2 4 8 — 2 5 0 6 3 Η ~ (CH2) 3〇Et yellow powder 1 7 5 — 1 7 8 6 4 Et nPr white powder 2 2 2-2 2 5 6 5 Et nBu yellow powder 1 S 〇-18 2 6 6 -CH2CH = CH2 -CH2CH = CH2 yellow powder 1 7 2-17 4 6 7 H-< ch2) 4oh brown powder 2 2 0-2 2 3 6 8-(CH2) 2OH-(CH2) 2〇H Brown powder 1 0 8-110 6 9 Me-(CH2) 2Ph White powder 1 9 0-19 3 7 0 Me iBu Yellow powder 1 7 8-18 1 7 1 H -C (Me2) CH2Ph White powder 1 9 0- 19 2 OH _ / 7 2 (Pale yellow crystal 2 3 3-2 3 4 N 1 Test result 1 Effect on myocardial contractility ^ Effect compound (synthesis example No.) Myocardial contractility conversion rate (%) 100 μM 300 μΜ 1 24.7 52.7 2 44,2 84.0 4 55.7 135.0 8 88.5 103.8 12 116.7 150.0 15 22.0 61.0 21 H.3 39.3 23 71.4 90.5 32 9.0 31.0 34 50.0 90.9 36 67.5 37 13.0 77.0 45 17.5 19.2 53 1,5 5.8 59 51, 9 148.5 60 22. 5 39.8 61 140.0 140.0 62 72.7 118.2 63 28.6 78.1 64 100.0 109.5 65 90.9 100.0 66 100.0 67 32.0 105.0 68 18.0 47.0 69 76.0 85.0 70 150.0 150.0 71 83.0 100.0 72 6.7 20.0 Test result 2 Change rate of heart white number ⑽ inu; 100 μΜ 300 μΜ 1 -17.7 -73.3 2 -12.8 -25.0 4 -Ί5.6 -53.8. 12 -50Q 15 -19.0 -34.0 21 -9.5 -19.0 23 -5.3 -21.1 32 -17.0 -52.0 34 -4.3 37 -1L0 -6.0 45 -3.5 -5.2 52 -65.0 53 -8.0 -28.2 59 -20.0 -47.5 60 -18.5 -40.0 • Amend this month a Supplement 86. 2. -δ No. δ3102877 Patent Application Supplementary Explanation Table ^ Additional Synthesis Examples (both osmic acid) „Synthesis Examples Ntt R1 R2 Melting point (X :) 6 1 nPr nPr White powder 1 7 3-1 8 3 6 2 Η nPr Yellow powder 2 4 8-2 5 0 6 3 Η -(CH2) 3〇Et yellow powder 1 7 5 — 1 7 S 6 4 Et nPr white powder '2 2 2-2 2 5 6 5 Et nBu yellow powder 1 8 〇- 18 2 6 6 -ch2ch = ch2 -CH2CH = CH2 yellow powder 1 7 2-17 4 6 7 Η-(CH2) 4OH brown powder 2 2 0 2 2 3 6 8-(CH2) 2OH-(CH2) 2OH brown powder 1 0 8-110 6 9 M e-(CH2) 2Ph White powder 1 9〇 一 19 3 7 0 Me JBu Yellow powder 1 7 8-18 1 7 1 H -C (Me2) CH2Ph White powder 1 9 0-1 9 2 Synthesis Example 6 1 7, 8 — Di · bao [—β, 6 —dimethyl — 7 —sheep — 8 _ Di · IE lactam-6H—_ South benzo [2,3 — f] benzo-1,1,2,3—D 咢Diazole

Add 7,8-diazepine-B »S-dimethyl-7,8-epoxy-6H-piperano [2,3-f] benzoone to a pressure-resistant glass tube of 1 O m Θ 2,1,3 — 219 mg (lmmo again) for two miles in mouth, 304 mg (3 mmoi?) Of di-n-diamine, acetaminophen, heat and stir at 1 50 C for 4 hours. After the reaction was completed, the reaction solution was saturated under reduced pressure. The resulting residue was subjected to silica gel chromatography (hexane: ethyl acetate = 9: 1) and the solvent was distilled off. Then, a sodium hydroxide-methanol solution was added to obtain the title compound as White powder basket acid basket 1 12m g (yield 3 5%). Financial accounting: 1 7 3 — 1 8 3. . Synthesis Example 6 2 7,8-Dihydro-6,6-dimethyl-1 7-Cyclo-8-n-propylamine-6 fluorene-Nanone [2,3-f] Benzo-2,1,3 — Mouth Beer 2

OH Me Me was carried out in the same manner as in Synthesis Example 61 using n-propylamine to obtain the title compound as a basket acid yellow powder. (Yield 5 6%)

Melting point: 248 — 25 ° C Synthesis Example 6 3 7,8-Digas-6,6-Dimethyl-7-Ethyl-8- (3, monoethoxypropyl) amino-6H —Pyrano [2,3-f] benzo-2,1,3-oroxadiazole

H (CHAOEt N

OH Me Me was carried out in the same manner as in Synthesis Example β1 using 3-ethoxypropylamine to obtain a pectic acid basket of the title compound as a yellow powder. (Yield: 56.6%) Melting point: 175—Synthetic example 6 4 7,8—Dihydro-6,6-dimethyl—7—Cyclo-8— (N —ethyl—N—n-propyl) Amino-6H-piperano [2,3-f] benzo-1,2,1,3-B 2nd beer 2

, 〇Η Me Me

Using N-ethyl-n-propylamine, the same operation as in Synthesis Example 61 was carried out to obtain the lotus compound containing the title compound as a white powder. (Yield: 3 5%) Melting ratio: 222- 225 C Synthesis example β 5 7 '8 — 2 — Θ * Θ — 2 1.A — Ύ — quarter to ^ 6 — 8 — (Ν — ethyl — Ν —N-propyl) amino-6 fluorene —anhydro [2,3 — fluorene] benzo-2,1,3 — mouth mile two miles

0H Me Me

Using N-ethyl-n-butylamine, the same operation as in Synthesis Example 61 was carried out to obtain the title compound as a yellow powder. (Yield: 2 8%) Melting point: 180— 182 ° C Synthesis Example 6 6 7, 8-Difluorene-6, 6-Dimethylmonofluorene—Meridine-8— (N, N—Dienyl) Amino-6 Η_piperano [2,3-f] is fused with 2,2,1,3 — mouth 咢 bisal CH2 = CHCH ^ n < CH2CH = CH2!

Using dienylamine, the same operation as in Synthesis Example 61 was carried out to obtain a disc acid basket of the title compound as a yellow powder. (Yield: 3 5%) Melting point: 172-174. . Synthesis Example 6 7 7,8-Dihydro-6,6-dimethyl-1 7-Cyclo-8- (4, -Cyclobutyl) amino-6H-Nano [2,3-f] benzo —2 * 1, 3 —D 咢 two miles

H, n / (CH2) 4OH

.OH Me Me •-, • Using 4-butylamine, the same operation as in Synthesis Example 61 was performed to obtain the title compound as a brown powder. (Yield: 4 9%)

Melting point: 220-223 ° C Synthesis Example 6 8 7,8—Dihydro-6,6-Dimethyl-7-Hydroxy-8— (Di-2′-Ethyl) amino-6H-Piran Benzo [2,3-f] benzo-1,2,1,3-narubi beer

H〇 (CH2) 2, n / (CH2) 2〇H

Using diethanolamine, the same operation as in Synthesis Example 61 was performed to obtain a basket acid basket of the title compound as a brown powder. (Yield: 43%) Melting point: 108—110. . Synthesis Example 6 9 7,8-Digas-6,6-Dimethyl-7-Chrysyl-8- (N-methyl-N-phenethyl) B-Amino-6H-Nanone [2,3 — F] benzo-2,1,3 —Doxadiazole

Using N-methylphenylethylamine *, the same operation as in Synthesis Example 61 was performed to obtain the acid compound basket 9 (yield: 79%) of the title compound as a white powder. Melting point: 190-193 ° C Synthesis Example 7 〇 7,8 —di * 璧 C — 6 * 6 —di 1 methyl — 7 —sheep to — 8 — (N —methyl—N — i —butyl) amino — 6 Η —pirano [2,3 — F] Benzo-2, 1, 3-P pyrene diran

Me, / Bu

.OH Me Me The same operation as in Synthesis Example 61 using methyl-i-butylamine was used to obtain the title compound as a yellow powder. (Yield 26%)

Melting point 181 ° C Synthesis Example 7 1 7,8—Digas-6,6—Dimethyl-7—Chrysene-8— (1 *, 1,1-Dimethylphenethyl) Methanyl-6 6 —? Π Nanac [2,3-f] Benzo-2,1,3-D— 2 miles

0, Me Me H C (Me) 2CH2Ph Using 1,1-dimethylphenethylamine, the same operation as in Synthesis Example 61 was carried out to obtain the title compound as a white powder. (Yield 34%)

Melting point: 190-192 ° C Test result 1 Effect on myocardial contractility Effect compound (synthesis example No.) Myocardial contractility conversion rate (%) 100 μM 300 μM 1 24.7 52.7 2 44.2 84.0 4 55.7 135.0 8 88.5 103.8 12 116.7 150.0 15 22.0 61.0 21 14.3 39.3 23 71.4 90.5 32 9.0 31.0 34 50.0 90.9 36 67.5 37 13.0 77.0 45 17.5 19.2 53 1.5 5.8 59 51.9 148.5 60 22.5 39.8 61 140.0 140.0 62 72.7 118.2 63 28.6 78.1 64 100.0 109.5 65 90.9 100.0 66 100.0 67 32.0 105.0 68 18.0 47.0 69 76.0 85.0 70 150.0 150.0 71 83.0 100.0 之 Detailed description of the method of measuring heart rate Test method for the effect of heart rate Take out the heart of a male Marmotte of Hartrey, and pass 959 ^ 0 2/5 〇 In the Krebs-Henseleit solution of 2 gas, the right atrium ° specimen was suspended in an FD pick up (TB-611T, Japan Optoelectronics Corporation) in an organ bus filled with nutrient solution maintained at 31 ° C. It is maintained by the resting tension of lg. The heartbeat count is determined by FD pick up, using the right atrial contraction measured by the preamplifier (AP-621G, Japan Optoelectronics) for distortion pressure as a starter, and using the preamplifier for instant heartbeat count ( AT-600G, Japan Optoelectronics Corporation) plus M measurement. The measured heart rate was recorded by a thermal recorder (WT-685G, Nippon Optoelectronics). First, after exchanging the nutrient solution while balancing, the maximum response to the accumulative adaptation of the sample M isoprotereno 1 (isoprotereno 1) was obtained. After being washed with isoproterenol and equilibrated for 60 minutes while exchanging the nutrient solution, the same sample was applied to each test compound to observe its effect. As a result, the effects of 100 am and 300 μm of each compound when applicable were obtained. The maximum response of isopropylpolyadrenaline obtained in advance by M was 100%, and the% change rate of M was shown.累积 The meaning of applying isoproterenol to specimens to obtain the maximum response: The standardization method that takes into account individual differences is generally used. The rationale for standardizing S84231 is to consider that, depending on the state of the specimen itself, the sensitivity of the drug will be different. The method is to obtain the maximum response (capability of each specimen) of isopropyl adrenaline heartbeat increase in advance according to different specimens. The size is 100%. The response of the test drug to be tested thereafter can be displayed as a ratio to its size, normalizing the individual difference in reactivity. The frequency pulse system is expressed as "heart value", and the Xu pulse system is expressed as minus value.

Claims (1)

S84S91 A8 B8 C8 D8 VI. Patent Application Fan Yuan No. 83 1 02877 Chinese Patent Application Amendment Scope of the Republic of China 8 / February, 2006 1. A pharmaceutical composition capable of enhancing myocardial contractility and reducing the number of heart beats, which is characterized by containing The compounds of the following formula (I) and the optical isomers of asymmetric carbon atoms at the 3 and 4 positions of the pyran ring, or a compound that can form amidine are pharmaceutically acceptable amidine as an effective ingredient , 03 /,-lV (please read the precautions on the back before filling this page) RU4 X2 -β T [where X1 and X2 are not present or represent an oxygen atom; X is an oxygen atom, a nitrogen atom, (the nitrogen atom may be replaced by a hydrogen atom or a CC 4 alkyl group); A is a hydrogen atom, Hydroxy or 0′C (0) R 5 (R 5 represents C 1 ~ C 4 fluorenyl); B represents hydrogen atom; _ R1 and R2 may be the same or different from each other and represent hydrogen atom or Ci-Cd alkyl group: R3 and R4 may be the same or different from each other, representing a hydrogen atom, an alkane of C i ~ C 6 (the alkyl group may be arbitrarily hydroxyl, Ci ~ C 4 alkoxy, or benzene. Paper standards are applicable to Chinese bacteria standards. (CNS) Α4 specification (210X297mm) -1-i Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs S84291 II D8 VI. Application for the replacement of the scope of patents), 〇2- (: 6_olefin-based or c (= Y ) ZR6 (Y represents oxygen atom, sulfur atom or NCN, Z represents NR9 (R9 represents Ci ~ C6 alkyl group), R6 represents hydrogen atom, or R3 and R4 together represent 1, 4 _ butyl or 1 , 5-pentyl (skeletal butyl or pentyl may be 'respectively. Arbitrarily substituted by a hydroxyl group), or R 3 and R represent (CH2) m X4 (CH2). {M and the meaning of 1 respectively , 2 or 3 'However, its total is 3 or 4, X4 represents. Shows _ oxygen atom, n. R 1 2 (R 12 represents phenyl)}, or R 3 and R 4 together (C Η 2) n ZC (= Υ) (η represents 2 or 3, Zn, Υ is the same definition as above)] 2. The pharmaceutical composition which can enhance the myocardial contractility and reduce the number of heart beats as described in the first patent application scope, which contains the following formula (II) The optically isomeric beer with the asymmetric carbon origins of the 3 and 4 positions of the compound shown in the pyran ring, or a compound that can form a hydrazone is a pharmaceutically acceptable hydrazone as an active ingredient , (Please read the notes on the back before filling out this page) I * 1. M In m Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (1D [where X s does not exist or represents an oxygen atom; X5 represents an oxygen atom, a nitrogen atom, (the nitrogen atom may be replaced by a hydrogen atom); tr ------ Q, it ——--------------- 384291 SI D8 々, patent application Fanyuan A1 means hydroxyl or 〇COCH3; B 1 means hydrogen atom ; R 13 and R 14 may be the same or different from each other to represent a hydrogen atom or a methyl group, an ethyl group; R 15 and R 16 may be the same or different from each other to represent a hydrogen atom, an alkyl group of Ci ~ C6 (the alkyl group may be any Substituted by, hydroxy, CiwCa alkoxy or phenyl) or C (= Υα) represents an oxygen atom, sulfur atom or N — CN, Z1 represents NR2 ° (R2. Represents a hydrogen atom, CC 6 alkyl), R 18 is a hydrogen atom Λ., Or R 15 and R16 together represent 14-butene or 1,5-pentyl (the butyl or pentenyl may be optionally substituted by a hydroxyl group, respectively), or R 15 And R 16 together represent (CH2) dX7 (CH2) p (0 and the mouth system respectively represent 1, 2 or 3, but the total is 3 or 4, X 7 represents an oxygen atom, and NR 23 (R 23 represents a phenyl group) ), Or R 15 and R 16—starting-indicating— (C Η 2) 3 NHC '(〇) —)] ° Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling in this (Page 3) If item 2 of the scope of patent application IT is a pharmaceutical composition that enhances myocardial contractility and reduces the number of heart beats. In formula (II) ..., R 15 is a hydrogen atom, R 16 is C (= Y2) NHR24 (Y2 represents an oxygen atom, sulfur Atom or N—CN, R 24 represents phenyl, benzyl or branched alkyl group which may be Ci ~ C 8). 4. If you apply for a pharmaceutical composition that enhances myocardial contractility and reduces the number of heart beats in item 2 of the scope of benefits, the formula (II). R 15 and R 16 together represent (CH 2) kN HC (= Y 3 ) (k is 2, 3 or _ 4, and Y 3 is a table showing oxygen atom, sulfur atom or N-CN). This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -3-'38429ΘΙ 郃 C8 D8 々, patent application scope (5. If the patent application scope item 2 can enhance myocardial contractility and reduce heart beat Number of pharmaceutical compositions, wherein R15 and R16 of formula (II) are both C 1 to C 6 fluorenyl groups. 6. For example, a phonopharmaceutical composition that can enhance myocardial contractility and reduce the number of beats of the heart, Wherein, R15 and R16 of the formula (II) together represent (CH 2) 4¾ (C Η 2) 5 〇 -------- ^ ί strike --------- order ----- · line (Please read the precautions on the back before filling out this page) The printed paper size of the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, China Standards (CNS) A4 (210X297 mm) -4--* 0 J α S. Application date April 1st, 1993 R Case No. ~~~ __ 83102877 Category (Amendment Supplementary Note: 84. Year β w Political 4 C4 Bulletin 384291 Bibian Patent Specification Invention Book Type _, Invention ^ Creator Chinese A medical composition capable of enhancing myocardial contractility and reducing heart beat beats Domicile's residence name (name) Masahiro Masahiro, Tochigawa, Masahiro, Masaru, Changjiro (1) Japan 0 Japan (3) Japan (1) Japan, Sanchime, Sanchome, Chiyoda-ku, Tokyo, Japan Inside the company (2) Ichisan Chemical Industry Co., Ltd., Ichisan Chemical Industry Co., Ltd., Hirai, Funabashi, Chiba, Japan (3) Ichisan Chemical Industry Co., Ltd., Ichisan Chemical Industry, Hirai, Hirai, Funabashi, Chiba, Japan Inside the institute: Nissan Chemical Industry Co., Ltd. Yusei Chemical Industry Co., Ltd. Binding of the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Consumption, Printing 2. Applicant's Nationality, Residence, Office (Office) Representative Surname: Yoshimoto, Tokyo, Japan, Chiyoda, Tokyo Kanda Nishiki-cho, Sanchomechi, Tokushima-shu, A-A scale is applicable _ Jia Jin Zhun (cns) Conglin (21QX297 public director) Line V. Description of the invention (4) C4 alkyl), phenyl (can be arbitrarily halogen Atom, hydroxyl, alkoxy optionally substituted), methyl, cyano or nitro substituted}, phenyl (optionally substituted by halogen atom, hydroxyl CL-C4 alkoxy is optionally substituted), R6 is a hydrogen atom, Ci-Ce is a linear or branched alkyl group {the alkyl group may be arbitrarily substituted by a halogen atom, a carboxyl group, C2 ~ (: 5 alkoxycarbonyl group, hydroxyl group , C! ~ C4 alkoxy, CH (OR) 2 (R stands for Ci-C4 alkyl), phenyl (can be arbitrarily substituted with halogen atom, hydroxyl, Ci-C # alkoxy), formamyl , Cyano or nitro substituted}, C2 ~ C6 linear or branched alkenyl {The alkene group can be optionally arbitrarily halogen atom, carboxyl, C 2 ~ C 5 oxycarbonyl, hydroxyl, Ci-Cd alkoxy Group, CH (OR) 2 (R represents Ci-Ci alkyl group), phenyl group (may be optionally substituted with halogen atom, hydroxyl group, (:, ~ (: 4 alkoxy group, optionally substituted), methyl amidyl group, cyanide Or nitro substituted}, C2 ~ C6 linear or branched block group {The alkynyl system can be optionally substituted by a halogen atom, a carboxyl group, a C 2 ~ C 5 alkoxycarbonyl group, a hydroxyl group, (: 1 ~ (: 4 Alkoxy, CH (OR) 2 (R stands for Cx-C4 alkyl), phenyl (optionally substituted with halogen atom, hydroxyl "Ci-Cd alkoxy), formamyl, cyano or Nitro substitution}, c3 Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative (please read the precautions on the back before filling this page) ~ C6 cycloalkyl {The cycloalkyl can be arbitrarily selected by halogen atom, carboxyl, C2 ~ C5 alkoxycarbonyl, hydroxyl, CiaCa alkoxy Group, CH (OR) 2 (R represents Ci—C4 alkyl group), phenyl group (optionally substituted by halogen atom, hydroxyl group, Ci-Ca alkoxy group) methylamino group, cyano group or nitro group} , Phenyl (optionally substituted with a halogen atom, fluorenyl, C:-C 4 alkoxy) or R 3 and R 4-together, 4-butylene or 1,5-pentyl { The butyl or pentyl separable paper size applies the Chinese National Standard (CNS) A4 specification (21CIX297 mm) ~~~~ Do not arbitrarily be Ca-C: 4 alkyl, taroyl (can be arbitrarily substituted with halogen atom, hydroxyl group, CiaC * oxygen group), halogen atom, V. Description of the invention (?) (Please read the notes on the back first Fill out this page again) 0R10 (R1. Represents a hydrogen atom, .Ci ~ c 4 alkyl, CORiMR11 represents Ci ~ c4 alkyl), nitro, s03H or P03Ρ2) arbitrary substitution}, or ruler 3 and 1 ^ 4 — starting from i, 4-butyl or 1 '5-pentyl {The butyl or pentoyl can be arbitrarily selected by C i ~ C 4 alkyl, phenyl (can be arbitrarily Prime atom, hydroxy 'CC 4 oxo optionally substituted), halogen atom, OR 10 (R 10 is a hydrogen atom, (^ ~ (^ alkyl, C0R11 (R11 is a c C 4 oxo)), nitro , S Ο 3Η or Ρ Ο 3Η 2) arbitrarily substituted}, or R 3 and R 4 together represent (c Η 2) mX 4 (C Η 2)! (M and again represent 1, 2, or 3, but Total 3, 4 or 5, CX4 represents oxygen atom, sulfur atom, NRI2 (R12 represents hydrogen atom "C 4 alkyl, phenyl (can be arbitrarily selected by halogen atom, hydroxyl, Cl ~ C4 alkoxy Replaced))) Or R3 and R4 together (CH2) nZC (= Υ) (η means 2, 3 or 4, ζ, Υ has the same definition as above)]. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Each substituent of the compound (1). In the present specification, "η-" means positive, "i" means different, "t —" means third, "c —" means ring, and "Me" means methyl, "Et" represents ethyl, "Pr" represents propyl, "Bu" represents butyl, "Pen" represents pentyl, "Hex" represents hexyl, and "Ph" represents phenyl. Examples of R1 and R2 may be hydrogen atoms , Me, E t, n— pr. This paper size applies Chinese National Standard (CNS) A4 specification (210.X 297 mm) 85 · 3 · Amendment A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs—M t • V »< · V. Description of the invention () 1 Complementary allowance 1 i — Pra η Β U, i — B u > S e C — B u and t — 1 1 | BU o and R 1 and R 2 together becomes (C Η 2) 4 or (c H 2) 5 with 1 I as a spiral ring. 0 Please Examples of 1 1 before 1 A are 0 Η > 0 c (〇) Μ e > 0 C (0) E t 、 read back 1 1 0 C (0) — n — ρ r > 0 c (0 ) — \ — P r 1 of surface I Note 0 C (0) n Β u > 0 c (〇) BU etc. 1 I 0 C (0) se C — B u, 0 C (O) t B uo Fill in this package again, A may sometimes be combined with B to indicate a single bond O Page 1 X Examples of oxygen atoms > sulfur atoms,. C (0) > C (S) > 1 IN Η > NM e, Ν Ε t, Ν-η — Pr, N — i — Pr, 1 1 IN — C -P r > Ν — η — Β u > Ν — 1 — BU > 1 1 Examples of N _ sec — BU > N — t — Β U and other O 1 R 3 and R 4 are hydrogen atom, M e, E t, n — Pr > 1 i — Pr, c — Pr > n —Β U > i — B u, 1 1 S ec —B u > t — Β u, η — P en, c — P en, 1, 4¾ η — H exc — Η e X, P h > benzyl p-chlorobenzyl, I p-fluorobenzyl > p-bromobenzyl, phenethyl, p-chlorophenethyl, p-fluorobenzene 1 1 I ethyl > p-bromophenethyl, c H 2 C 0 2 Η > c H 2 C 0 2 M e > 1 _ 1 1 C Η 2 C 0 2 E t > (c H 2) 2 C 0 2 Μ € ', 1 1 (CH 2) 2 C 0 2 ET, (C Η 2) 2C Η (0 M e) 2, 1 1 (CH 2) 2 C Η (〇Ε t) 2 , 1 1 (CH 2) 3 〇Η (CH 2) 3 0 Μ e (C Η 2) 3 0 E t 1 I (C Η 2) 3 C 1 > (C Η 2) 3 Β r (C Η 2) 3 F 、 1 1 I (c H 2) 3 C 〇2 Η, (CH 2) 3 C 0 2 M e 、 1 1 This paper size applies Chinese National Standard (CNS) Α4 specification (210.X297 mm ) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 8'5. March 3-7, 2015 Amended 5. Description of the invention (1) (C Η 2) 3 c 0 2 E t, CH) 3C H (Μ e) 2, (C Η 2) 3 c H (E t) 2, C (0) 0 M e, C (0) 0 E t, C (0) 0 n-P r, C (〇) 0 — i — P r C (〇) 0 — c — Pr > C (0) 0 — n — B uc (0) 0 — i — Β u, C (0 ) 0 — sec — BUC (0) 0 — t — BU, C (0) 0 — n — P en C (0) 〇 — C — P en, C (0) 0 — n — H e X > c (0) 0 — C — H ex, C (0) 0 (c H 2) 2 c 1, C (0) 0 (CH 2) 2b r > C (0) 0 (CH 2) 3 c 1 > C (0) 0 (c H 2) 3 B r > c (0) 0 ρ h > C (0) 0 c H 2] P h > C (0) NHM e, C (0) NHE t, C (0) NH — n — P r, c (0) N Η — i-P Γ Λ C (0) NH-c — P r, c (0) N Η — η — B u, C ( 0) NH — i — B u, c (0) N Η — sec —B u > C (〇) NH — t — BU, C (0) Ν Η — n — P en, C (0) NH — c — P en > C (〇) NH — n — H e X, c (〇) Ν Η — c-He X > C (〇) NH (c H 2) 2 c C (0) NH (c H 2) 2 B r > C (0) NH (c H 2) 3 C 1 > C (0) NH (c H 2) 3 B rc (〇) Ν Η P h > C ( 0) NHGH 2F h 、 C (0) NHC (0) CC 3 (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210.X297 mm)-installed · Order A7 B7 3, -7 Amendment Supplement V. Description of Invention (? ), C (S) NHMe, C (S) NHEt, C (S> NH— n-Pr, C (S) NH— i-Pr, (Please read the precautions on the back before filling this page) C (S ) NH-c-Pr, C (S) NH-n-Bu, C (S) NH-i- Bu, C (S) NH-sec- Bu, C (S) NH- t-Bu, C (S ) NH- n-Pen, C (S) NH-c- Pen, C (S) NH-n-Hex, C (S) NH- c- Hex, C (S) NH (CH2) 2C1, C (S ) NH (CH2) 2Br, C (S) NH (CH2) 3C1, C (S) NH (CH2) 3Br, C (S) N Η Ph, C (S) NHCH2Ph, C (N — CN) NHMe, C (N-CN) NHBt, C (N — CN) NH-n-Pr, C (N-CN) NH-i-Pr, C (N-CN) NH-c-Pr > C (N-CN ) NH-n-Bu > C (N-CN) NH- i-Bu, printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (C-N-CN) t -Bu > C (N — CN — NH-n-Pen, C (N-CN) NH-c-Pen > C (N-CN) NH-n-Hex, C (N-CN) NH- c-Hex > C (N-CN) NH (CH2) 2C 1. This paper size is applicable to China National Standard (CNS) A4 specification (2IQX297 mm) A7 85. 3 .-7 repair ilL __ ^ _ B7__ is a a. 5. Description of the invention () L === —- ™ C (N-CN) NH (CH2) 2Br, C (N — CN) NH (CH2) 3C1, C (N-CN) NH (CH2) 3Br, C (N-CN) HNPh > C (N-CN) NHCH2Ph or R3 and R4 together with the N atom combined with these represent the following Q1 ~ Q3 6. (Please read the precautions on the back and fill out this page first.) Binding. Order.1 Printed on the paper by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The paper size applies to Chinese National Standards (CNS) Α4 specifications (21QX 297 mm) A7 B7 V. Invention Description (/ &) Q27 • Me Factory M,. Factory NH (n 乂 ο, 乂 S NCN Q30 Q28 Q26 Ν 人. people. Q29 Q34 Q35 Q33 (Please read the precautions on the back before filling this page) • Q36 * Ν NCN I * 1T Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, the pharmaceutical composition of the present invention can enhance the myocardial contractility and reduce the number of heart beats, which contains the compound represented by the following formula (II) and its pyran Optical isomers of asymmetric carbon atoms at the 3rd and 4th positions of the ring, or those that can form pharmaceutically acceptable compounds as effective ingredients, RlU6 (ID [where X6 is not present or represents an oxygen atom; this paper size applies to the Chinese national standard (milk) 8 4 specifications (210 '/ 297 mm) 5. Description of the invention (A7 B7 Assist. 3 ·-* 1 Modification-year, month and year », nitrogen atom (this nitrogen atom may be replaced by a hydrogen atom X 5 represents an oxygen atom); A 1 represents a hydrogen atom represents a CC 4 alkyl group; B 1 represents a hydrogen atom; R 13 And R 14 may be the same or different from each other and represent a hydrogen atom or a C i ~ C 4 alkyl group; R 15 and R 16 may be the same or different from each other and represent a hydrogen atom; the alkyl group of C i ~ Cs {The alkyl system may Optionally substituted by hydroxy, Cl ~ c4 alkoxy or phenyl) or C (^ Y1) represents an oxygen atom, sulfur atom or N-CN, Z1 represents nr20 (R2〇 represents a gas atom, an alkyl group ), Rw is a hydrogen atom, or R15 and R · 16 together represent 1,4-butylene or 1,5-pentyl (the butyl or pentyl group may be optionally substituted with a fluorenyl group, respectively), Or R1S and R16—. (CH2) 〇X7 (CH2) p (0 and p represent 1, 2, or 3 respectively, but the total is 3 or 4, X7 represents an oxygen atom, via a radical or 〇C (〇 ) R17 (R17 series ( (Please read the notes on the back before filling this page) Packing. Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (R23 represents phenyl), or R15 and Rw together represent _ (CH2) 3NHC (0)-)] ° In the pharmaceutical composition capable of enhancing myocardial contractility and reducing cardiac pulse number of the present invention, in formula (II), R15 is a hydrogen atom and R16 is C (= Y2) NHR24 (Y2 represents an oxygen atom, a sulfur atom, or N- CN, R24 means phenyl, benzyl, or branched alkyl NR 2 to Ci ~ C8 NR 2 3 The medicine group of the present invention which can enhance the myocardial contractility and reduce the number of heart beats The paper size is applicable to Chinese national standards ( CNS) A4 specification (21QX297 mm) 5. Description of the invention (A7 B7 85. 3.-7 —year-month supplementary Γ compound, its formula (II) R15 and R16 together represent (CH2) k NHC (= Υ 3) (k represents 2, 3 or 4, and Υ 3 represents an oxygen atom, a sulfur atom, or N—CN). The pharmaceutical composition of the present invention, which can enhance myocardial contractility and reduce the number of heart beats, wherein formula (II) R15 and R16 are both Ci ~ c6 alkyl. The medicine of the present invention can enhance myocardial contractility and reduce heart beat Composition, R15 of formula (I I) of the, R16 - represents from (CH2) 4 or (C Η 2) 5. The following Examples illustrate the compounds of the present invention, X 1 and X 2 of the absent. In addition, Ci'Ti is as defined above. Qn == (R 3 —) (R4 —.) N — 0 means (Please read the notes on the back before filling this page.) Printed by the Central Standards Bureau staff consumer cooperatives CD The paper size is applicable to China National Standard (CNS) A4 specification (210.X297 mm)-u- Dazheng: .t1 ^ Supplement No. 83i〇2877 patent application supplementary explanation form (sincerity; ... |. | Daojia's Fencheng examples (> > all 塩 acid acid 塩) Synthesis example No. R1 R2 Melting point of properties ( C) 6 1 nPr nPr white powder 1 7 3 — 1 8 3 6 2 Η nPr yellow powder 2 4 8-2 5 0 6 3 Η-(CH2) 3〇Et yellow powder 1 7 5 _ 1 7 8 5 4 Εΐ nPr white powder 2 2 2-2 2 5 6 5 Et nBu yellow powder 1 8 〇-1 8 2 6 6 -ch2ch = ch2 -CH2CH = CH2 yellow powder 1 7 2-1 7 4 6 7 Η (ch2) 4oh Brown powder 2 2 0 — 2 2 3, 6 δ-(CH2) 2OH-(CH2) 2〇H Brown powder 1 0 S — 1 1 0 6 9 Me-(CH2) 2Ph White powder 1 9 0-1 9 3 7 0 Me JBu yellow powder 1 7 8-1 8 1 7 1 H -C (Me2) CH2Ph white powder 1 9 0-1 9 2 OH 7 2 Γ IS light yellow crystal 2 3 3-2 3 4 .i.- Supplement No. 83102877 Patent Application Table i plus Synthesis Example r1 is osmic acid) Synthesis Example No. R1 R2 Properties Melting point (t :) 6 1 nPr nPr White powder 1 7 3-18 3 6 2 Η nPr Yellow powder 2 4 8 — 2 5 0 6 3 Η ~ (CH2) 3〇Et yellow powder 1 7 5 — 1 7 8 6 4 Et nPr white powder 2 2 2-2 2 5 6 5 Et nBu yellow powder 1 S 〇-18 2 6 6 -CH2CH = CH2 -CH2CH = CH2 yellow powder 1 7 2-17 4 6 7 H-< ch2) 4oh brown powder 2 2 0-2 2 3 6 8-(CH2) 2OH-(CH2) 2〇H Brown powder 1 0 8-110 6 9 Me-(CH2) 2Ph White powder 1 9 0-19 3 7 0 Me iBu Yellow powder 1 7 8-18 1 7 1 H -C (Me2) CH2Ph White powder 1 9 0- 19 2 OH _ / 7 2 (Pale yellow crystal 2 3 3-2 3 4 N 1 • Corrected this month a Supplement 86. 2. -δ No. δ3102877 Patent Application Supplementary Explanation Table ^ Additional Synthesis Examples (all are osmic acid塩) „Synthesis example Ntt R1 R2 Melting point (X :) 6 1 nPr nPr White powder 1 7 3-1 8 3 6 2 Η nPr Yellow powder 2 4 8-2 5 0 6 3 Η-(CH2) 3〇Et Yellow powder 1 7 5 — 1 7 S 6 4 Et nPr White powder '2 2 2-2 2 5 6 5 Et nBu yellow powder 1 8 〇-18 2 6 6 -ch2ch = ch2 -CH2CH = CH2 yellow powder 1 7 2-17 4 6 7 Η-(CH2) 4OH brown powder 2 2 〇 2 2 3 6 8-(CH2) 2OH-(CH2) 2OH Brown powder 1 0 8-110 6 9 Me-(CH2) 2Ph White powder 1 9 〇19 19 3 7 0 Me JBu Yellow powder 1 7 8-18 1 7 1 H -C (Me2) CH2Ph White powder 1 9 0-1 9 2 Test result 1 Effect on myocardial contractility Effect compound (synthesis example No.) Myocardial contractility conversion rate (%) 100 μM 300 μM 1 24.7 52.7 2 44.2 84.0 4 55.7 135.0 8 88.5 103.8 12 116.7 150.0 15 22.0 61.0 21 14.3 39.3 23 71.4 90.5 32 9.0 31.0 34 50.0 90.9 36 67.5 37 13.0 77.0 45 17.5 19.2 53 1.5 5.8 59 51.9 148.5 60 22.5 39.8 61 140.0 140.0 62 72.7 118.2 63 28.6 78.1 64 100.0 109.5 65 90.9 100.0 66 100.0 67 32.0 105.0 68 18.0 47.0 69 76.0 85.0 70 150.0 150.0 71 83.0 100.0 or nitrogen 1 pulse H, show heart. Ο son. Table and. It is suggested that Epoxy I is used as the oxane or 'Qiangji A table c4, and 3' is the isocentric, σ oxygen XΛ group. Constriction shows that C-alkanes are collected as 'tables', ce and other muscles do ARIR2 or atoms ~ basal center with ^ β a. The hydrogen C stretching force stored in the hydrogen source 1 pentamine does not indicate, -strong low 2 | Table 5 Sexual X′—N, .Ν—χZ One point B is the original, toxic, R ammonia 1 and 1 base _, shown, the substance 'oxygen 1' epidermal combination 1 '醯 R Dinghua XC / R4 extension and so on. I this subtraction 1 sub 3 4 number c C original R 'pat. Driving · No. 83102877 Patent Application Chinese Manual Amendment Page February 1986 Yu Zheng, Zhong Zhang Summary of the Invention (Name of the invention: a medicinal composition capable of enhancing myocardial contractility and reducing heart beat rate) The present invention relates to a compound represented by the following formula (I), or when it can be formed into a pharmaceutically acceptable compound: Cardiotonic medicine with active ingredients. Abstract of the English invention (Name of the invention: Disclosed are cardiotonic medicines containing, as the active ingredient, at least one of compounds 〇 £ fprmula (I) and their phara & cologically acceptable salts when they £ 〇πα salts. (Please read the notes on the back before filling Γ: · each column of the page) -s 0 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs not exist or represents an orygen aton; A represents OH ox: a C ·, acyloxy group? * B represents a hydrogen • j atooi or may a chemical bond along with λ; X i £ an oxygen atom, nitrogen, sulfuretc .; R 'and H1 each represents a hydrogen atom, λ C, -C4 alkyl group,' etc .; R_ and R4 each represents a hydro ^ an atom, a Ct-C4 aikyl group , etc., or they may together form a 1, Ί-batylene or 1, S-pentylene group. The compounds have a strong activity 〇 £ reinforcing the contraction of cardiac nueciefi and a strong activity of reducinfl the rate of heart beats · As th6y afe not toxic ,, they ace useful as cardiotOQic medlcicves. This paper size applies to Chinese national standards (CNS > A4 specifications (210X297 mm) -2- S84S91 A8 B8 C8 D8 VI. Patent Application Fan Yuan No. 83 1 02877 Chinese Patent Application Amendment Scope of the Republic of China 8 / February, 2006 1. A pharmaceutical composition capable of enhancing myocardial contractility and reducing the number of heart beats, which is characterized by containing The compounds of the following formula (I) and the optical isomers of asymmetric carbon atoms at the 3 and 4 positions of the pyran ring, or a compound that can form amidine are pharmaceutically acceptable amidine as an effective ingredient , 03 /,-lV (please read the precautions on the back before filling this page) RU4 X2 -β T [where X1 and X2 are not present or represent an oxygen atom; X is an oxygen atom, a nitrogen atom, (the nitrogen atom may be replaced by a hydrogen atom or a CC 4 alkyl group); A is a hydrogen atom, Hydroxy or 0′C (0) R 5 (R 5 represents C 1 ~ C 4 fluorenyl); B represents hydrogen atom; _ R1 and R2 may be the same or different from each other and represent hydrogen atom or Ci-Cd alkyl group: R3 and R4 may be the same or different from each other, representing a hydrogen atom, an alkane of C i ~ C 6 (the alkyl group may be arbitrarily hydroxyl, Ci ~ C 4 alkoxy, or benzene. Paper standards are applicable to Chinese bacteria standards. (CNS) Α4 size (210X297 mm) -1-i Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs